View source for Hypersensitivity

{{short description|Overreaction of the immune system to an antigen}}
{{other uses}}
{{Infobox medical condition
| name            = Hypersensitivity
| image           =2228 Immune Hypersensitivity new.jpg

| caption         =Types of hypersensitivity reactions

| field           = [[Immunology]]
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'''Hypersensitivity''' (also called '''hypersensitivity reaction''') is an immune response characterized by mechanisms that cause significant tissue damage or physiological dysfunction, whether directed against [[pathogen]]s, harmless environmental [[antigen]]s, or self-antigens that is reproducible upon re-exposure to the antigen.<ref>{{Cite journal |last1=Andreozzi |first1=Laura |last2=Giannetti |first2=Arianna |last3=Cipriani |first3=Francesca |last4=Caffarelli |first4=Carlo |last5=Mastrorilli |first5=Carla |last6=Ricci |first6=Giampaolo |date=2019 |title=Hypersensitivity reactions to food and drug additives: problem or myth? |url=https://www.mattioli1885journals.com/index.php/actabiomedica/article/view/8168 |journal=Acta Bio-Medica |volume=90 |issue=3–S |pages=80–90 |doi=10.23750/abm.v90i3-S.8168 |issn=2531-6745 |pmc=6502174 |pmid=30830065}}</ref><ref>{{Cite journal |last1=Gargano |first1=Domenico |last2=Appanna |first2=Ramapraba |last3=Santonicola |first3=Antonella |last4=De Bartolomeis |first4=Fabio |last5=Stellato |first5=Cristiana |last6=Cianferoni |first6=Antonella |last7=Casolaro |first7=Vincenzo |last8=Iovino |first8=Paola |date=2021 |title=Food Allergy and Intolerance: A Narrative Review on Nutritional Concerns |journal=Nutrients |volume=13 |issue=5 |page=1638 |doi=10.3390/nu13051638 |issn=2072-6643 |pmc=8152468 |pmid=34068047 |doi-access=free }}</ref> While hypersensitivity mechanisms can sometimes serve protective functions (such as control of infectious diseases), they are distinguished by their capacity to cause collateral tissue damage that may exceed any protective benefit. Collectively, hypersensitivities are extremely common: [[hay fever]] affects about 1 in 10 people worldwide,<ref>{{Cite journal |last1=Dykewicz |first1=Mark S. |last2=Hamilos |first2=Daniel L. |date=February 2010 |title=Rhinitis and sinusitis |url=https://linkinghub.elsevier.com/retrieve/pii/S0091674909028814 |journal=Journal of Allergy and Clinical Immunology |language=en |volume=125 |issue=2 |pages=S103–S115 |doi=10.1016/j.jaci.2009.12.989 |pmid=20176255 |url-access=subscription }}</ref> [[asthma]] affects hundreds of millions,<ref>{{Cite journal |last1=Wang |first1=Zhufeng |last2=Li |first2=Yun |last3=Gao |first3=Yi |last4=Fu |first4=Yu |last5=Lin |first5=Junfeng |last6=Lei |first6=Xuedong |last7=Zheng |first7=Jinping |last8=Jiang |first8=Mei |date=2023-06-23 |title=Global, regional, and national burden of asthma and its attributable risk factors from 1990 to 2019: a systematic analysis for the Global Burden of Disease Study 2019 |journal=Respiratory Research |volume=24 |issue=1 |page=169 |doi=10.1186/s12931-023-02475-6 |doi-access=free |issn=1465-993X |pmc=10288698 |pmid=37353829}}</ref> and about 1 in 12 people have an autoimmune disease.<ref>{{Cite journal |last1=Fairweather |first1=DeLisa |last2=Frisancho-Kiss |first2=Sylvia |last3=Rose |first3=Noel R. |date=2008-09-01 |title=Sex Differences in Autoimmune Disease from a Pathological Perspective |url=https://ajp.amjpathol.org/article/S0002-9440(10)61635-5/fulltext |journal=The American Journal of Pathology |language=English |volume=173 |issue=3 |pages=600–609 |doi=10.2353/ajpath.2008.071008 |issn=0002-9440 |pmid=18688037 |pmc=2527069 }}</ref>

In 1963, [[Philip George Houthem Gell]] and [[Robin Coombs]] introduced a systematic classification of the different types of hypersensitivity based on the types of antigens and immune responses involved.<ref>{{Cite journal |last=Silverstein |first=Arthur M. |date= 2003|title=Philip George Houthem Gell. 20 October 1914 – 3 May 2001 Elected FRS 1969 |url=https://royalsocietypublishing.org/doi/10.1098/rsbm.2003.0010 |journal=Biographical Memoirs of Fellows of the Royal Society |language=en |volume=49 |pages=163–178 |doi=10.1098/rsbm.2003.0010 |pmid=14989267 |issn=0080-4606|url-access=subscription }}</ref> According to this system, known as the [[#Gell and Coombs classification|Gell and Coombs classification]]<ref>{{Cite journal |last1=Descotes |first1=J. |last2=Choquet-Kastylevsky |first2=G. |date=2001-02-02 |title=Gell and Coombs's classification: is it still valid? |url=https://www.sciencedirect.com/science/article/abs/pii/S0300483X00004005 |journal=Toxicology |volume=158 |issue=1–2 |pages=43–49 |doi=10.1016/s0300-483x(00)00400-5 |issn=0300-483X |pmid=11164991|bibcode=2001Toxgy.158...43D |url-access=subscription }}</ref> or Gell-Coombs's classification,<ref>{{Cite journal |last=Rajan |first=T. V. |date=2003 |title=The Gell-Coombs classification of hypersensitivity reactions: a re-interpretation |url=https://www.cell.com/trends/immunology/fulltext/S1471-4906(03)00142-X?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS147149060300142X%3Fshowall%3Dtrue |journal=Trends in Immunology |volume=24 |issue=7 |pages=376–379 |doi=10.1016/s1471-4906(03)00142-x |issn=1471-4906 |pmid=12860528|url-access=subscription }}</ref> there are four types of hypersensitivity:

# [[Type I hypersensitivity|Type I]], which is an [[Immunoglobulin E]] (IgE)-mediated immediate reaction.
# [[Type II hypersensitivity|Type II]], an antibody-mediated reaction canonically involving [[IgG]], [[IgM]], or both.
# [[Type III hypersensitivity|Type III]], an [[immune complex]]-mediated reaction involving [[IgG]], [[complement system]] and [[phagocytes]]. 
# [[Type IV hypersensitivity|Type IV]], a [[T cells|T cell]]-mediated, delayed hypersensitivity reaction.<ref name="TypeIII">{{Citation|last1=Usman|first1=Norina|title=Type III Hypersensitivity Reaction|date=2021|url=https://www.ncbi.nlm.nih.gov/books/NBK559122/|work=StatPearls|place=Treasure Island (FL)|publisher=StatPearls Publishing|pmid=32644548|access-date=2021-07-05|last2=Annamaraju|first2=Pavan}} {{CC-notice|cc=by4}}</ref>

In addition to their different mechanisms, each one differs in the time to symptoms following exposure to the offending [[antigen]]. Type I hypersensitivity is also known as immediate hypersensitivity because it occurs within seconds to minutes of exposure. Type II (cytotoxic) and type III (immune complex) occur within hours of exposure. Type IV is also known as delayed-type hypersensitivity (DTH) and occurs days after exposure.

''Note: The Gell-Coombs classification of hypersensitivities (as well as the other ones discussed on this page) does not correspond to the modern classification of immune responses as [[Th1 cell|type 1]], [[Th2|type 2]], or [[T helper 17 cell|type 3]]. Type I hypersensitivities, for example, are inappropriate manifestations of type 2 immune responses (IgE, IL-4, IL-13-driven). Type IV are type 1 immune responses (IFN-γ, Th1, CD8 T cell-driven), when considering the original Gell-Coombs classification system. Type II and III can involve a mixture of different immune response types.''

[[Autoimmune disease]]s manifest as some form of type II, III, or IV hypersensitivity reaction as their key pathological process. It is possible to have multiple types of hypersensitivity reaction contribute to a disease at the same time, and the type of hypersensitivity reaction central to a given immunological disease can change over time (for example, acute [[hypersensitivity pneumonitis]] is thought to be a type III hypersensitivity, but as it becomes more chronic, it begins to become resemble type IV more), or even by region (allergic asthma behaves like a type IV hypersensitivity in the lower airways and like a type I hypersensitivity in the upper respiratory tract).<ref name=":8" /> Thus, these categories are best viewed as guides rather than absolute rules.

An understanding of hypersensitivity reactions is important in guiding diagnostic and treatment decisions for the conditions that are mediated by them.

==Terminology==
The term "[[allergy]]" has undergone significant revision over the years, originally referring specifically to type I hypersensitivities (i.e., an IgE-mediated process). However, modern professional societies define allergy to be any immunologic mechanism (whether IgE-mediated or not) that produces a hypersensitivity reaction.<ref>{{Cite journal |last1=Tanno |first1=Luciana Kase |last2=Calderon |first2=Moises A. |last3=Smith |first3=Helen E. |last4=Sanchez-Borges |first4=Mario |last5=Sheikh |first5=Aziz |last6=Demoly |first6=Pascal |last7=Joint Allergy Academies |date=2016 |title=Dissemination of definitions and concepts of allergic and hypersensitivity conditions |journal=The World Allergy Organization Journal |volume=9 |article-number=24 |doi=10.1186/s40413-016-0115-2 |doi-access=free |issn=1939-4551 |pmc=4977713 |pmid=27551327}}</ref> This has some use because some things often described as allergies or allergic diseases (e.g., [[nickel allergy]], [[Food protein-induced enterocolitis syndrome|FPIES]]) are not type I hypersensitivity reactions. However, this means that anything under the Gell and Coombs classification can be considered an allergy, so long as the antigen being targeted by the hypersensitivity originates from outside the body (i.e., not autoimmune diseases).<ref name=":8" /> There are also non-immune hypersensitivity reactions included in classifications under more modern frameworks (type V, VI, and VII hypersensitivity under EAACI 2023 position paper classification, see below), which are not covered under Gell and Coombs's classification. These represent non-allergic hypersensitivity reactions. Despite this, many still use the term allergy specifically to describe type I hypersensitivity reactions, so it is best to obtain clarification whenever possible. Confusingly, the term "allergen" has not been updated to reflect this change in usage,<ref>{{Cite journal |last1=Dramburg |first1=Stephanie |last2=Hilger |first2=Christiane |last3=Santos |first3=Alexandra F. |last4=de las Vecillas |first4=Leticia |last5=Aalberse |first5=Rob C. |last6=Acevedo |first6=Nathalie |last7=Aglas |first7=Lorenz |last8=Altmann |first8=Friedrich |last9=Arruda |first9=Karla L. |last10=Asero |first10=Riccardo |last11=Ballmer-Weber |first11=Barbara |last12=Barber |first12=Domingo |last13=Beyer |first13=Kirsten |last14=Biedermann |first14=Tilo |last15=Bilo |first15=Maria Beatrice |date=2023 |title=EAACI Molecular Allergology User's Guide 2.0 |url=https://onlinelibrary.wiley.com/doi/abs/10.1111/pai.13854 |journal=Pediatric Allergy and Immunology |language=en |volume=34 |issue=S28 |article-number=e13854 |doi=10.1111/pai.13854 |pmid=37186333 |issn=1399-3038|hdl=10044/1/106144 |hdl-access=free }}</ref> and specifically refers to any antigen bound by IgE.

==Gell and Coombs classification==
The Gell and Coombs classification of hypersensitivity is the most widely used, and distinguishes four types of immune response that result in bystander tissue damage on the basis of their mechanism.<ref>{{Cite journal|date=July 2008|title=Davidson's Principles and Practice of Medicine, IE Edition, 20th Ed: Medicine—Clinical Medicine|journal=Journal of Endocrinology, Metabolism and Diabetes of South Africa|language=en|volume=13|issue=2|page=75|doi=10.1080/22201009.2008.10872174|issn=1608-9677|s2cid=220276722|doi-access=free}}</ref>
{| class="wikitable sortable"
|+Gell and Coombs Hypersensitivity Reactions Classification
!     Type     !! style="width: 150px" | Alternative names     !! style="width: 120px" | Antibodies or Cell Mediators      !!     Immunologic Reaction    
!Timing!!     Clinical Examples
(some conditions involve multiple types of hypersensitivity reactions simultaneously)
|-

! [[Type I hypersensitivity|I]]
|
* Immediate
||IgE, mast cells
| Before a type I hypersensitivity reaction may occur, [[Sensitization (immunology)|sensitization]] is required to produce [[antigen]] ([[allergen]])-specific IgE.

# Secreted IgE binds to the [[FCER1|high-affinity IgE receptor]] on the surface of [[mast cell]]s, [[basophil]]s, and potentially [[eosinophil]]s. IgE is predominantly bound to the surface of mast cells because of the strength of the association ([[Protein-ligand binding|K<sub>D</sub>]] ≈ 10<sup>−10</sup> M<ref name=":0">{{Cite book |title=Middleton's allergy: principles and practice |date=2020 |publisher=Elsevier |isbn=978-0-323-54424-5 |editor-last=Burks |editor-first=A. Wesley |location=Edinburgh London New York |editor-last2=Bacharier |editor-first2=Leonard B. |editor-last3=Holgate |editor-first3=Stephen T. |editor-last4=Hershey |editor-first4=Gurjit K. Khurana |editor-last5=O'Hehir |editor-first5=Robyn E. |editor-last6=Broide |editor-first6=David H. |editor-last7=Stokes Peebles |editor-first7=R.}}</ref>), and levels in the circulation are minimal.
# Allergen is bound by membrane-bound IgE. 
# IgE-allergen complex is sensed by mast cells, basophils, and eosinophils. 
# Mast cells (as well as basophils) [[Degranulation|degranulate]], liberating key [[Vasoactivity|vasoactive]] mediators such as [[histamine]], [[leukotriene]]s, as well as [[tryptase]], [[platelet-activating factor]], and [[heparin]] (among other substances). Mast cells are the principal tissue effector cells in type I reactions.
|Rapidly upon exposure to the allergen (seconds to minutes, typically).||
* [[allergic rhinitis]] 
* [[food allergy]]
* [[Hives|urticaria]]/[[angioedema]] 
* venom allergy
* [[drug allergy]]
* IgE-mediated [[anaphylaxis]]
* [[Alpha-gal syndrome|α-gal syndrome]] (delayed onset of symptoms relative to exposure)
|-
! [[Type II hypersensitivity|II]]
|
* [[antibody-dependent cell-mediated cytotoxicity|Antibody-dependent]]
* Cytotoxic
||IgG, IgM, complement, FcγRs, phagocytes, NK cells
| Type II reactions are formed against cell surface or matrix antigens.

# Surface-bound antigen is recognized by pre-formed IgG or IgM antibodies.
# Classical pathway of complement activation is initiated on the surface of the cell.
# Complement activation produces opsonins that can be recognized by complement receptor-expressing phagocytes. 
# Membrane attack complex forms a pore in the cell.
# Antibody-dependent cellular cytotoxicity may occur via FcγR-dependent mechanisms.

In some cases, the antibody may have an [[agonist]]ic function, as in Graves disease, in which antibodies target and activate the TSH receptor, inducing hyperthyroidism.

Otherwise, the antibodies may exert a blocking function, as in myasthenia gravis, in which antibodies against the [[Acetylcholine receptor|acetylcholine receptor (AchR)]] or [[MuSK protein|muscle-specific kinase (MusK)]] prevent interactions with their target ligand. 
|Hours–days after re-exposure. ||
* [[Autoimmune hemolytic anemia]]
* [[Rheumatic heart disease]]
* [[Erythroblastosis fetalis]]
* [[Goodpasture's syndrome]]
* [[Graves' disease]] (agonistic antibodies)
* [[Myasthenia gravis]] (blocking antibodies)
* [[Pemphigus vulgaris]]
* Drug-induced [[cytopenia]]
|-
! [[Type III hypersensitivity|III]]
|
* [[Immune complex]]
||Immune complexes (IgG, IgA, IgM), complement, FcγRs
| Type III hypersensitivities occur in response to soluble antigens.

# Antigen–antibody complexes form in excess and deposit in vessel walls and other tissues e.g., the synovium. 
# Complement activation generates anaphylatoxins that recruit and activate neutrophils. 
# Neutrophil enzymes and ROS cause vasculitis and tissue injury.

Type III is distinguished from type II also on the basis of the fact that it is driven by immune complex deposition, whereas type II hypersensitivity does not depend on the deposition of immune complexes. 
|Hours to days after re-exposure.||
* [[Serum sickness]] 
* [[Arthus reaction]]
* [[Post streptococcal glomerulonephritis]]
* [[Membranous nephropathy]]
* [[Reactive arthritis]]
* [[Lupus nephritis]]
* [[Systemic lupus erythematosus]]
* [[Hypersensitivity pneumonitis]]
|-
! [[Type IV hypersensitivity|IV]]

|
* Delayed<ref name=":1">{{cite journal |pmid=10673450 |url=http://escholarship.org/uc/item/2fw0g1xx |year=1999 |last1=Black |first1=C. A. |title=Delayed type hypersensitivity: Current theories with an historic perspective |journal=Dermatology Online Journal |volume=5 |issue=1 |page=7 |doi=10.5070/D32FW0G1XX |url-access=subscription }}</ref><ref name=":2">{{EMedicine|article|136118|Delayed Hypersensitivity Reactions}}</ref>
||
* [[T-cells]]
** [[Cytotoxic T cell]]s (CTLs)
** [[T helper cell]]s
| CTLs and T helper cells are activated by an antigen presenting cell. When the antigen is presented again in the future, the memory T cells will be activated and cause an inflammatory response mediated by the effector cells activated by the T cells (e.g., CTLs, neutrophils, macrophages, eosinophils) and the cytokines produced.<ref name="LeTau">Le, Tau. First Aid for the USMLE Step 1 2013, p. 203-204</ref> The classical version of type IV hypersensitivity is demonstrated with the tuberculin skin test, which is a Th1-driven reaction.  
'''In modernized versions of the Gell and Coombs framework, there are 4 subtypes of type IV hypersensitivity which are driven by type 1 immune responses (IVa), type 2 immune responses (IVb), cytotoxicity (IVc), and type 3 immune responses (IVd).'''
|Delayed; peaks ~48–72 hours after re-exposure. ||
* [[Contact dermatitis]]
* [[Mantoux test]]
* [[Chronic transplant rejection]]
* [[Coeliac disease]]
* [[Hashimoto's thyroiditis]]
* [[Granuloma annulare]]
|}
These are elaborated upon in greater depth below in their respective sections.

=== Classifications beyond Gell & Coombs ===
''Note: The numerals used between the two frameworks presented below (EAACI 2023 and Pichler) overlap, but are not identical i.e., IVc in EAACI is not the same as IVc under Pichler's classification.''

==== EAACI Proposed Categorization of Hypersensitivity reactions ====
Over time, additional types of hypersensitivity reactions have been defined beyond the 4 proposed by Gell and Coombs.<ref name=":8">{{Cite journal |last1=Jutel |first1=Marek |last2=Agache |first2=Ioana |last3=Zemelka-Wiacek |first3=Magdalena |last4=Akdis |first4=Mübeccel |last5=Chivato |first5=Tomás |last6=Del Giacco |first6=Stefano |last7=Gajdanowicz |first7=Pawel |last8=Gracia |first8=Ibon Eguiluz |last9=Klimek |first9=Ludger |last10=Lauerma |first10=Antti |last11=Ollert |first11=Markus |last12=O'Mahony |first12=Liam |last13=Schwarze |first13=Jürgen |last14=Shamji |first14=Mohamed H. |last15=Skypala |first15=Isabel |date=November 2023 |title=Nomenclature of allergic diseases and hypersensitivity reactions: Adapted to modern needs: An EAACI position paper |journal=Allergy |volume=78 |issue=11 |pages=2851–2874 |doi=10.1111/all.15889 |issn=1398-9995 |pmid=37814905 |hdl=20.500.11820/c4c9bded-3cde-469c-acb1-03bd073d2665 |hdl-access=free }}</ref> Per the most recent classification published by European Academy of Allergy and Clinical Immunology in 2023 in their position paper, hypersensitivities are classified as per the table below (type I-III are the same as in the Gell and Coombs classification, type IV is expanded, and types V-VII are new). Note that type IV hypersensitivities in this framework are not exactly the same as those in modernized Gell and Coombs' taxonomy. Because types I, II, and III are the same as with Gell and Coombs, the table below begins with type IVa to minimize redundancy. EAACI 2023 groups type I-III hypersensitivities as antibody-mediated.
{| class="wikitable"
|+EAACI 2023 Hypersensitivity Reaction Classifications
!Group 
!Class
!Critical Mediators
!Mechanism
!Timing
!Clinical Examples
(some conditions involve multiple types of hypersensitivity reactions simultaneously)
|-
|'''Cell-mediated'''
|Type IVa
(cell-mediated, [[Type 1 immunity|type 1]])
|Th1 cells, IFN-γ, activated macrophages
|
# Antigen is presented to memory Th1/Tc1 cells. 
# These cells release IFN-γ and related mediators that activate macrophages. 
# Local induration and, with persistence, granuloma-type pathology develops. 
|Delayed; peaks ~48–72 h. 
|
* [[Mantoux test|Tuberculin skin test]] 
* chronic phase of [[hypersensitivity pneumonitis]]
* [[Coeliac disease|celiac disease]]
* some [[contact dermatitis]] patterns
* non-type 2 [[Asthma|endotypes of asthma]] 
|-
|'''Cell-mediated'''
|Type IVb
(cell-mediated, [[Th2|type 2]])
|Th2 cells, IL-4, IL-5, IL-13, eosinophils
|
# Antigen presentation favors Th2 responses. 
# Th2 cytokines recruit and activate eosinophils and can drive IgE class switching. 
# Eosinophil-rich inflammation leads to tissue symptoms and chronicity.

There is significant overlap between  type IVa hypersensitivity and type I hypersensitivity in terms of the mechanisms and players involved. The major distinctions lie in timing and the predominant role of eosinophilic inflammation via IL-5 in type IVb but not type I hypersensitivity reactions. The synthesis of IgE occurs at the end stage of type IVb hypersensitivity, whereas it is a prerequisite for type I hypersensitivity to occur. However, specific reactions may include features of both e.g., acute bronchospasm in asthma is often type I, but the chronic phase with eosinophilia and persistent inflammation via Th2s and ILC2s is more similar to type IVb. Type IVb hypersensitivity can also induce dysfunction of the epithelial barrier as in type V hypersensitivity.
|Usually days–weeks; often chronic relapsing. 
|
* [[Atopic dermatitis]] endotypes 
* [[asthma]]/[[Chronic rhinosinusitis|CRS]] T2 endotypes 
* [[eosinophilic esophagitis]] 
* [[Drug rash with eosinophilia and systemic symptoms|DRESS]] 
|-
|'''Cell-mediated'''
|Type IVc
(cell-mediated, [[T helper 17 cell|type 3]])
|T-cell–derived chemokines (e.g., CXCL8/IL-8), GM-CSF, neutrophils
|
# Antigen presentation elicits Th17/Tc17 responses. 
# IL-17–family signals recruit and activate neutrophils and local innate pathways. 
# Neutrophil enzymes and extracellular traps contribute to epithelial injury. 
|Delayed; typically days (drug-related patterns accelerate on re-challenge). 
|
* Neutrophilic asthma endotypes
* neutrophil-predominant dermatitis variants. Note'':'' some drug eruptions historically labeled "Type IVd" in other taxonomies are included here in the EAACI scheme. 
|-
|'''Tissue-driven mechanisms'''
|Type V
(epithelial)
|Epithelial barrier defects, TSLP, IL-33, IL-25, ILC2/Th2 pathways
|
# Barrier disruption increases allergen and microbe access. 
# Epithelial signals activate downstream immune pathways and sustain inflammation.
# Chronic disease reflects ongoing barrier dysfunction with mixed immune features.

In type V hypersensitivity, immunological dysfunction occurs downstream of barrier dysfunction. Loss of barrier integrity itself induces recruitment of immune cells. For example, mutations in filaggrin predispose to multiple allergic diseases (most prominently atopic dermatitis) regardless of pre-existing atopy.

Some immunologists contest whether this represents a distinct type of hypersensitivity or just a predisposing factor to hypersensitivity.
|Chronic with exposure-triggered flares. 
|
* atopic dermatitis
* allergic rhinitis
* chronic rhinosinusitis with nasal polyps 
* asthma 
* eosinophilic esophagitis 
* celiac disease 
* [[Protein losing enteropathy|protein-losing enteropathy]]
|-
|'''Tissue-driven mechanisms'''
|Type VI
(metabolic)
|Adipokines (e.g., leptin), innate cytokines (e.g., IL-6, TNF-α), oxidative stress
|
# Obesity and related metabolic states create systemic low-grade inflammation. 
# This milieu modifies airway/tissue immunity and disease endotypes.
# Severity and treatment response can be altered.

Note that this is not saying that obesity or metabolic disorders are themselves a hypersensitivity reaction, but rather that they produce conditions that induce type VI hypersensitivity (metaflammation<ref>{{Cite journal |last=Hotamisligil |first=Gökhan S. |date=February 2017 |title=Inflammation, metaflammation and immunometabolic disorders |url=https://www.nature.com/articles/nature21363 |journal=Nature |language=en |volume=542 |issue=7640 |pages=177–185 |doi=10.1038/nature21363 |pmid=28179656 |bibcode=2017Natur.542..177H |issn=1476-4687|url-access=subscription }}</ref>). The EAACI regards type VI hypersensitivity more as a modifier of existing hypersensitivity reactions (for example, obese asthmatics are more likely to be corticosteroid-resistant than nonobese asthmatics, in part because the milieu pushes towards neutrophilic endotypes) rather than a distinct type of hypersensitivity.
|Chronic; tracks with metabolic stress. 
|
* Obesity-associated asthma phenotypes and related airway disease
|-
|'''Direct response to chemicals'''
|Type VII
|[[Leukotriene|cysteinyl-leukotrienes]], mast cells 
|Multiple, depending on the substance in question. Classic examples:

* [[Cyclooxygenase-1|COX-1]] inhibition results in enhanced production of cysteinyl-leukotrienes causing bronchoconstriction
* Mast cells are activated directly by [[MRGPRX2]]<nowiki/>ligands, ion channels, or other GPCR ligands independently of IgE
|Minutes–hours. 
|
* [[Aspirin-exacerbated respiratory disease|AERD/N-ERD]]
* [[Pseudoallergy|Non-allergic hypersensitivity reaction (formerly known as pseudoallergy)]]
|}
The expansion reflects recognition that not all adverse immune reactions fit the original antibody/cell-mediated dichotomy, particularly chronic inflammatory conditions with complex pathophysiology.

==== Pichler Drug Hypersensitivity Classifications ====
Another classification that has seen use other than Gell and Coombs is that proposed by Pichler,<ref>{{Cite journal |last1=Pichler |first1=Werner J. |last2=Adam |first2=Jaqueline |last3=Daubner |first3=Barbara |last4=Gentinetta |first4=Thomas |last5=Keller |first5=Monika |last6=Yerly |first6=Daniel |date=2010-07-01 |title=Drug Hypersensitivity Reactions: Pathomechanism and Clinical Symptoms |url=https://www.sciencedirect.com/science/article/pii/S0025712510000556 |journal=Medical Clinics of North America |volume=94 |issue=4 |pages=645–664 |doi=10.1016/j.mcna.2010.04.003 |pmid=20609855 |issn=0025-7125|url-access=subscription }}</ref><ref>{{Cite journal |last=Pichler |first=Werner J. |date=2019 |title=Immune pathomechanism and classification of drug hypersensitivity |url=https://onlinelibrary.wiley.com/doi/abs/10.1111/all.13765 |journal=Allergy |language=en |volume=74 |issue=8 |pages=1457–1471 |doi=10.1111/all.13765 |pmid=30843233 |issn=1398-9995}}</ref> mainly for drug hypersensitivities. This is an important update because drug hypersensitivities do not operate under the exact same rules as hypersensitivities to other substances. For example, drugs are often small molecules and are recognized only as haptens, hypersensitivity reactions to drugs don't always require prior sensitization (meaning they can occur from the first exposure), and host genetics/pharmacogenomics play an outsized role. It is broadly similar to the Gell and Coombs classification with some slight refinements in that it subdivides type IV into type IVa, IVb, IVc, and IVd, adds non-allergic hypersensitivity, and pharmacological interaction with immune receptor (p-i reaction). Those that differ from the Gell and Coombs classification are summarized below.
{| class="wikitable"
|+Pichler Additional Hypersensitivity Classification
!Type
!Mechanism
!Timing
!Clinical Example
|-
|'''IVa (Th1/macrophage predominant)'''
|
# Drug (or haptenated self-peptide) is presented to Th1/Tc1 cells. 
# IFN-γ and related mediators activate macrophages and cause induration. 
# With persistence, a delayed-type pattern develops. 
|Delayed; peaks ~48–72 h (sometimes later).
|
* [[Mantoux test|Tuberculin skin test]]
* some [[contact dermatitis]] patterns
|-
|'''IVb (Th2/eosinophil predominant)'''
|
# Antigen presentation biases a Th2 response. 
# IL-4/IL-5/IL-13 recruit eosinophils and can promote IgE class switching. 
# Eosinophil-rich inflammation produces edema and systemic findings (e.g., eosinophilia). 
|Usually days–weeks; often prolonged or relapsing. 
|
* Morbilliform/maculopapular exanthema
* DRESS (2–6 wk after start). 
|-
|'''IVc (cytotoxic T cell predominant)'''
|
# Drug-specific CD8⁺ T cells recognize drug-modified peptide–HLA or drug–HLA/TCR complexes. 
# Perforin/granzyme and granulysin induce keratinocyte apoptosis/necrosis. 
# Epidermal injury can become widespread. 
|Typically 1–3 wk after first course; faster on re-exposure
|
* [[Stevens–Johnson syndrome|Stevens-Johnson Syndrome]]/[[Toxic epidermal necrolysis|Toxic Epidermal Necrolysis]]
|-
|'''IVd (Th17/neutrophil predominant)'''
|
# Drug-specific T cells produce chemokines (e.g., CXCL8) and GM-CSF. 
# Recruited neutrophils release enzymes and extracellular traps. 
# Sterile pustules and epithelial injury result, resolving after withdrawal. 
|Delayed; often 24–72 h; accelerates on re-challenge. 
|
* [[Acute generalized exanthematous pustulosis|Acute generalized exanthematous pustulosis (AGEP)]]
* neutrophil-predominant drug dermatitis variants. 
|-
|'''p-i (pharmacological interaction with immune receptor)'''
|
# Without covalent [[hapten]]ation, the drug binds reversibly to HLA and/or the T-cell receptor and directly activates T cells. 
# Reactions can occur on the first course. 
# Strong HLA associations reflect structural binding requirements. 
|Days–weeks on first course; can be rapid; faster on re-exposure. 
|
* Abacavir hypersensitivity (HLA-B57:01)
* carbamazepine SJS/TEN (HLA-B15:02 in many Asian populations) 
* allopurinol SCAR (HLA-B*58:01). 
|-
|'''non-allergic hypersensitivity reaction'''
|Multiple mechanisms:

* MRGPRX2-mediated direct mast-cell activation causes immediate mediator release without IgE. 
* COX-1 inhibition skews arachidonic metabolism toward cysteinyl-leukotrienes, provoking bronchoconstriction and nasal/airway inflammation. 
* Complement activation–related pseudo-allergy (CARPA) generates C3a/C5a that activate leukocytes and mast cells.
* Bradykinin-mediated angioedema (e.g., ACE inhibitors) reflects impaired bradykinin degradation.

Among others.
|Minutes–hours (often on first exposure). 
|
* [[Red man syndrome (Drug eruption)|Vancomycin infusion]] [[Red man syndrome (Drug eruption)|syndrome]] (formerly called red man syndrome)
* [[Aspirin-exacerbated respiratory disease|AERD]]/N-ERD to NSAIDs
* IV iron/liposomal drugs (CARPA)
* ACE-inhibitor angioedema (bradykinin). 
|}
Importantly, there are additional classification schemes for [[adverse drug reaction]]s, but these do not generally consider them in terms of hypersensitivity mechanisms.

These classification schemes are constantly being revised and updated across geographies and specialties.

== Type I hypersensitivity ==

{{Main|Type I hypersensitivity}}
Type I hypersensitivities are commonly described as allergies (see note in Terminology).

=== Pathogenesis ===
[[File:Type I Hypersensitivity.webm|thumb|Type I hypersensitivity]]
The essential component of type I hypersensitivity is high-[[Binding affinity|affinity]] antigen-specific immunoglobulin E (IgE). There are essentially no restrictions on what antigen IgE may be generated against (despite the need for [[Immunoglobulin class switching|class-switching]], IgE against carbohydrate allergens [[Alpha-gal syndrome|has been observed]], as well as against haptens), but common ones include various food allergens, latex, venoms, and medications. IgE accounts for a minority of all immunoglobulins produced, and, under physiological conditions, helps to mediate protection against parasites (those too large to get inside cells e.g., [[helminths]], [[arthropod]]s) as well as [[venom]]s.<ref>{{Cite journal |last1=Palm |first1=Noah W. |last2=Rosenstein |first2=Rachel K. |last3=Medzhitov |first3=Ruslan |date=April 2012 |title=Allergic host defences |journal=Nature |language=en |volume=484 |issue=7395 |pages=465–472 |doi=10.1038/nature11047 |pmid=22538607 |pmc=3596087 |bibcode=2012Natur.484..465P |issn=1476-4687}}</ref> The mechanisms underlying the induction of IgE are not completely understood, but it is known that IgE can be produced either from class switching directly from an IgM antibody or through sequential class switching (in which an IgG antibody made from an IgM antibody class switches into IgE).<ref>{{Cite journal |last1=Koenig |first1=Joshua F. E. |last2=Wade-Vallance |first2=Adam K. |last3=Jiménez-Saiz |first3=Rodrigo |last4=Bruton |first4=Kelly |last5=Gadkar |first5=Siyon |last6=Grydziuszko |first6=Emily |last7=Walker |first7=Tina D. |last8=Gordon |first8=Melissa E. |last9=Gillgrass |first9=Amy E. |last10=Taylor |first10=Justin J. |last11=Waserman |first11=Susan |last12=Jordana |first12=Manel |date=2025 |title=Allergic Reactivity and Memory Occur Independently of Sequential Switching Through IgG1 |journal=Allergy |language=en |volume=80 |issue=8 |pages=2141–2157 |doi=10.1111/all.16460 |issn=1398-9995 |pmc=12368767 |pmid=39803817}}</ref> The generation of an IgE antibody against an antigen is known as [[Sensitization (immunology)|sensitization]]. This is much more likely to occur in [[Atopy|atopic]] individuals. Sensitization on its own does not guarantee that a type I hypersensitivity reaction will occur.

Once the IgE has been generated, it binds primarily to mast cells via the [[FCER1|high-affinity IgE receptor (FcεRI)]] expressed on mast cells and basophils. Mast cells reside in the tissues (the skin and the mucosae) whereas basophils are bloodborne. Only very small quantities of IgE are present in the sera and their half-life in sera is brief. However, when bound to mast cells as a complex with FcεRI, IgE can persist for weeks, independent of whether or not it is being actively produced by IgE-secreting cells.<ref>{{Cite journal |last1=Lawrence |first1=Monica G. |last2=Woodfolk |first2=Judith A. |last3=Schuyler |first3=Alexander J. |last4=Stillman |first4=Leland C. |last5=Chapman |first5=Martin D. |last6=Platts-Mills |first6=Thomas A. E. |date=February 2017 |title=Half-life of IgE in serum and skin: Consequences for anti-IgE therapy in patients with allergic disease |journal=The Journal of Allergy and Clinical Immunology |volume=139 |issue=2 |pages=422–428.e4 |doi=10.1016/j.jaci.2016.04.056 |issn=1097-6825 |pmc=5405770 |pmid=27496596}}</ref>

The onset of symptoms from exposure occurs in seconds to minutes. Once the antigen (allergen) IgE is specific against makes contact with [[FCER1|FcεRI]]-bound IgE, it induces an influx of calcium into the mast cell via [[ORAI1]] that causes degranulation and releases the following mediators (functions listed are not comprehensive):

* '''[[Histamine]]''' - Causing enhanced vascular permeability, mucus secretion and bronchoconstriction.
* '''[[Heparin]]''' - Functions as an anticoagulant, binds mediators, and sequesters growth factors.
* '''[[Tryptase]]''' - Degrades allergens and cross-linked IgE, activates complement, degrades neuropeptides, and increases airway smooth muscle contractility.
* '''[[Chymase]]''' - Expression of chymase is mast cell subset-specific: it is present in human MC<sub>TC</sub> (human tryptase and chymase-containing mast cells) and mouse CTMC (connective tissue mast cells). Chymase increases mucus secretion, activates [[Interleukin 1 beta|IL-1β]], and degrades [[extracellular matrix]].

After this initial release of preformed mediators, mast cells begin to synthesize:

* '''[[Prostaglandin D2|PGD2]]''' - Causing bronchoconstriction, tissue edema, increased mucus secretion, and chemotaxis of eosinophils, Th2 cells, and basophils via the [[Prostaglandin DP2 receptor|CRTH2 (CD294)]] receptor.
* '''[[Leukotriene|LTC4/LTD4]]''' - Causing bronchoconstriction, tissue edema, increased mucus secretion, enhanced IL-13-dependent airway smooth muscle proliferation, eosinophil IL-4 secretion, mast cell IL-5, IL-8, and TNF-α secretion, and tissue fibrosis.

The role of [[Platelet-activating factor|platelet-activating factor (PAF)]] as an amplifier of mast cell responses has been increasingly recognized,<ref>{{Cite journal |last1=Kajiwara |first1=Naoki |last2=Sasaki |first2=Tomomi |last3=Bradding |first3=Peter |last4=Cruse |first4=Glenn |last5=Sagara |first5=Hironori |last6=Ohmori |first6=Kazumitsu |last7=Saito |first7=Hirohisa |last8=Ra |first8=Chisei |last9=Okayama |first9=Yoshimichi |date=May 2010 |title=Activation of human mast cells through the platelet-activating factor receptor |journal=Journal of Allergy and Clinical Immunology |volume=125 |issue=5 |pages=1137–1145.e6 |doi=10.1016/j.jaci.2010.01.056 |pmid=20392487 |issn=0091-6749}}</ref><ref>{{Cite journal |last1=Petersen |first1=Lars J. |last2=Church |first2=Martin K. |last3=Skov |first3=Per S. |date=May 1997 |title=Platelet-activating factor induces histamine release from human skin mast cells in vivo, which is reduced by local nerve blockade |journal=Journal of Allergy and Clinical Immunology |volume=99 |issue=5 |pages=640–647 |doi=10.1016/s0091-6749(97)70026-5 |pmid=9155831 |issn=0091-6749}}</ref> particularly in [[anaphylaxis]].<ref>{{Cite journal |last1=Vadas |first1=Peter |last2=Gold |first2=Milton |last3=Perelman |first3=Boris |last4=Liss |first4=Gary M. |last5=Lack |first5=Gideon |last6=Blyth |first6=Thomas |last7=Simons |first7=F. Estelle R. |last8=Simons |first8=Keith J. |last9=Cass |first9=Dan |last10=Yeung |first10=Jupiter |date=2008-01-03 |title=Platelet-Activating Factor, PAF Acetylhydrolase, and Severe Anaphylaxis |url=https://www.nejm.org/doi/full/10.1056/NEJMoa070030 |journal=New England Journal of Medicine |volume=358 |issue=1 |pages=28–35 |doi=10.1056/NEJMoa070030 |pmid=18172172 |issn=0028-4793}}</ref> The PAF may be produced directly by the mast cells themselves,<ref>{{Cite journal |last1=Triggiani |first1=M. |last2=Hubbard |first2=W. C. |last3=Chilton |first3=F. H. |date=1990-06-15 |title=Synthesis of 1-acyl-2-acetyl-sn-glycero-3-phosphocholine by an enriched preparation of the human lung mast cell |journal=Journal of Immunology (Baltimore, Md.: 1950) |volume=144 |issue=12 |pages=4773–4780 |doi=10.4049/jimmunol.144.12.4773 |issn=0022-1767 |pmid=2141044}}</ref> but other sources are not excluded. While type I hypersensitivity reactions share these common pathomechanisms, distinct ones are also possible (for example, [[bradykinin]] contributes to anaphylaxis and [[angioedema]], but is not prominent as a general feature of type I hypersensitivity reactions as a whole and is not a mast cell mediator<ref>{{Cite journal |last1=Sala-Cunill |first1=Anna |last2=Björkqvist |first2=Jenny |last3=Senter |first3=Riccardo |last4=Guilarte |first4=Mar |last5=Cardona |first5=Victoria |last6=Labrador |first6=Moises |last7=Nickel |first7=Katrin F. |last8=Butler |first8=Lynn |last9=Luengo |first9=Olga |last10=Kumar |first10=Parvin |last11=Labberton |first11=Linda |last12=Long |first12=Andy |last13=Di Gennaro |first13=Antonio |last14=Kenne |first14=Ellinor |last15=Jämsä |first15=Anne |date=April 2015 |title=Plasma contact system activation drives anaphylaxis in severe mast cell–mediated allergic reactions |url=https://linkinghub.elsevier.com/retrieve/pii/S0091674914011117 |journal=Journal of Allergy and Clinical Immunology |language=en |volume=135 |issue=4 |pages=1031–1043.e6 |doi=10.1016/j.jaci.2014.07.057 |pmid=25240785 |url-access=subscription }}</ref>). Many reactions also evolve a late phase (hours) characterized by recruited eosinophils and sustained mediator/cytokine production.

Hypersensitivity reactions mediated by IgE antibodies may occur upon first exposure to a substance when prior sensitization to homologous antigens from other sources has occurred; this cross-reactivity explains the onset of symptoms even without previous direct contact.<ref>{{Cite journal |title=IgE-based analysis of sensitization and cross-reactivity to yellow mealworm and edible insect allergens before their widespread dietary introduction |author=Majsiak, Emilia; Choina, Magdalena; Gromek, Weronika; Wykrota, Julia; Kozłowska, Danuta; Swadźba, Jakub; Cukrowska, Bożena; Kowal, Krzysztof |journal=Scientific Reports |year=2025 |volume=15 |issue=1 |article-number=1466 |doi=10.1038/s41598-024-83645-4 |pmid=39789064 |pmc=11718154 |bibcode=2025NatSR..15.1466E }}</ref> However, most of the time,  type I hypersensitivity reactions believed to be the result of a first exposure actually reflect an undetected prior exposure to the antigen that induced sensitization.

Note that [[scombroid food poisoning]] is not a type I hypersensitivity, but rather a direct histamine toxicity, as IgE is not involved.

=== Diagnosis ===
Type I hypersensitivities may be diagnosed through multiple modalities. For example, the gold-standard for food allergies is the double-blind placebo controlled food challenge (DBPCFC).<ref>{{Cite journal |last1=Bird |first1=J. Andrew |last2=Leonard |first2=Stephanie |last3=Groetch |first3=Marion |last4=Assa'ad |first4=Amal |last5=Cianferoni |first5=Antonella |last6=Clark |first6=April |last7=Crain |first7=Maria |last8=Fausnight |first8=Tracy |last9=Fleischer |first9=David |last10=Green |first10=Todd |last11=Greenhawt |first11=Matthew |last12=Herbert |first12=Linda |last13=Lanser |first13=Bruce J. |last14=Mikhail |first14=Irene |last15=Mustafa |first15=Shahzad |date=2020-01-01 |title=Conducting an Oral Food Challenge: An Update to the 2009 Adverse Reactions to Foods Committee Work Group Report |url=https://www.jaci-inpractice.org/article/S2213-2198(19)30855-4/abstract |journal=The Journal of Allergy and Clinical Immunology: In Practice |language=English |volume=8 |issue=1 |pages=75–90.e17 |doi=10.1016/j.jaip.2019.09.029 |issn=2213-2198 |pmid=31950914}}</ref> The presence of IgE antibodies alone is never sufficient to demonstrate the existence of a type I hypersensitivity reaction.<ref>{{Cite journal |last1=Venter |first1=Carina |last2=Halken |first2=Susanne |last3=Toniolo |first3=Alice |last4=Nowak-Wegrzyn |first4=Anna |last5=Vlieg-Boerstra |first5=Berber |last6=Nilsson |first6=Caroline A. |last7=Fleischer |first7=David M. |last8=Silva |first8=Debra de |last9=Barber |first9=Domingo |last10=Khaleva |first10=Ekaterina |last11=Knol |first11=Edward |last12=Protudjer |first12=Jennifer L. P. |last13=Morandini |first13=Laura |last14=Muraro |first14=Antonella |last15=Smith |first15=Pete |date=2025-11-01 |title=Diagnosing IgE-mediated food allergy: How to apply the latest guidelines in clinical practice |url=https://www.jaci-global.org/article/S2772-8293(25)00157-2/fulltext |journal=Journal of Allergy and Clinical Immunology: Global |language=English |volume=4 |issue=4 |article-number=100556 |doi=10.1016/j.jacig.2025.100556 |issn=2772-8293 |pmid=40989752 |pmc=12452672 }}</ref> This must be paired with a clinical history supportive of the reaction, as it otherwise may reflect sensitization and trigger avoidance of an allergen that is not necessary, and, paradoxically, may lead to the development of type I hypersensitivity.<ref>{{Cite journal |last1=Toit |first1=George Du |last2=Roberts |first2=Graham |last3=Sayre |first3=Peter H. |last4=Bahnson |first4=Henry T. |last5=Radulovic |first5=Suzana |last6=Santos |first6=Alexandra F. |last7=Brough |first7=Helen A. |last8=Phippard |first8=Deborah |last9=Basting |first9=Monica |last10=Feeney |first10=Mary |last11=Turcanu |first11=Victor |last12=Sever |first12=Michelle L. |last13=Lorenzo |first13=Margarita Gomez |last14=Plaut |first14=Marshall |last15=Lack |first15=Gideon |date=2015-02-26 |title=Randomized Trial of Peanut Consumption in Infants at Risk for Peanut Allergy |journal=New England Journal of Medicine |volume=372 |issue=9 |pages=803–813 |doi=10.1056/NEJMoa1414850 |pmid=25705822 |pmc=4416404 |issn=0028-4793}}</ref> This underscores the importance of appropriate supervision before attempting elimination diets. For medications, the equivalent of a DBPCFC is a graded dose provocation test. Otherwise, skin prick testing can also diagnose type I hypersensitivities, but reflects sensitization rather than true hypersensitivity and must be paired with a supportive clinical history. The basophil activation test is occasionally used as a complement to other testing, but it has important limitations that warrant consideration, including the potential for nonresponders and the inaccessibility.<ref>{{Cite journal |last1=Ebo |first1=Didier G. |last2=Bridts |first2=Chris H. |last3=Mertens |first3=Christel H. |last4=Sabato |first4=Vito |date=2021-04-01 |title=Principles, potential, and limitations of ex vivo basophil activation by flow cytometry in allergology: A narrative review |url=https://www.sciencedirect.com/science/article/pii/S0091674920315529 |journal=Journal of Allergy and Clinical Immunology |volume=147 |issue=4 |pages=1143–1153 |doi=10.1016/j.jaci.2020.10.027 |pmid=33152367 |issn=0091-6749|url-access=subscription }}</ref> Component-resolved diagnostics allow for identification of the specific allergenic component of substances that triggers type I hypersensitivity, which can help inform treatment.<ref>{{Cite journal |last1=Borres |first1=Magnus P. |last2=Maruyama |first2=Nobuyuki |last3=Sato |first3=Sakura |last4=Ebisawa |first4=Motohiro |date=2016-10-01 |title=Recent advances in component resolved diagnosis in food allergy |url=https://www.sciencedirect.com/science/article/pii/S1323893016301010 |journal=Allergology International |volume=65 |issue=4 |pages=378–387 |doi=10.1016/j.alit.2016.07.002 |pmid=27543004 |issn=1323-8930}}</ref> Test choice and interpretation should follow [[Pre- and post-test probability|pretest probability]] to minimize false positives and false negatives.

=== Management ===
Histamine is a central mediator of the symptoms observed in type I hypersensitivity reactions, and so treatment with [[antihistamine]]s often provides effective symptomatic relief.<ref>{{Cite journal |last1=Linton |first1=Sophia |last2=Hossenbaccus |first2=Lubnaa |last3=Ellis |first3=Anne K. |date=2023-10-01 |title=Evidence-based use of antihistamines for treatment of allergic conditions |url=https://www.annallergy.org/article/S1081-1206(23)00524-0/fulltext |journal=Annals of Allergy, Asthma & Immunology |language=English |volume=131 |issue=4 |pages=412–420 |doi=10.1016/j.anai.2023.07.019 |issn=1081-1206 |pmid=37517656}}</ref> Corticosteroids can also help to promote an immunoregulatory environment that helps suppress the inflammation associated with type I hypersensitivities.<ref>{{Cite journal |last1=Cain |first1=Derek W. |last2=Cidlowski |first2=John A. |date=April 2017 |title=Immune regulation by glucocorticoids |journal=Nature Reviews. Immunology |volume=17 |issue=4 |pages=233–247 |doi=10.1038/nri.2017.1 |issn=1474-1741 |pmc=9761406 |pmid=28192415}}</ref> However, histamine is not the only mediator, nor is it necessarily the most important one. For instance, antihistamines neither prevent nor treat anaphylaxis, indicating a key role for other mediators (intramuscular epinephrine is the first-line treatment for anaphylaxis and it addresses all of its pathological manifestations).<ref>{{Cite journal |last1=Golden |first1=David B. K. |last2=Wang |first2=Julie |last3=Waserman |first3=Susan |last4=Akin |first4=Cem |last5=Campbell |first5=Ronna L. |last6=Ellis |first6=Anne K. |last7=Greenhawt |first7=Matthew |last8=Lang |first8=David M. |last9=Ledford |first9=Dennis K. |last10=Lieberman |first10=Jay |last11=Oppenheimer |first11=John |last12=Shaker |first12=Marcus S. |last13=Wallace |first13=Dana V. |last14=Abrams |first14=Elissa M. |last15=Bernstein |first15=Jonathan A. |date=2024-02-01 |title=Anaphylaxis: A 2023 practice parameter update |url=https://www.annallergy.org/article/S1081-1206(23)01304-2/fulltext |journal=Annals of Allergy, Asthma & Immunology |language=English |volume=132 |issue=2 |pages=124–176 |doi=10.1016/j.anai.2023.09.015 |issn=1081-1206 |pmid=38108678}}</ref><ref>{{Cite journal |last1=Shaker |first1=Marcus S. |last2=Wallace |first2=Dana V. |last3=Golden |first3=David B. K. |last4=Oppenheimer |first4=John |last5=Bernstein |first5=Jonathan A. |last6=Campbell |first6=Ronna L. |last7=Dinakar |first7=Chitra |last8=Ellis |first8=Anne |last9=Greenhawt |first9=Matthew |last10=Khan |first10=David A. |last11=Lang |first11=David M. |last12=Lang |first12=Eddy S. |last13=Lieberman |first13=Jay A. |last14=Portnoy |first14=Jay |last15=Rank |first15=Matthew A. |date=2020-04-01 |title=Anaphylaxis—a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis |url=https://www.jacionline.org/article/S0091-6749(20)30105-6/fulltext |journal=Journal of Allergy and Clinical Immunology |language=English |volume=145 |issue=4 |pages=1082–1123 |doi=10.1016/j.jaci.2020.01.017 |issn=0091-6749 |pmid=32001253}}</ref> Premedication with antihistamines and corticosteroids to prevent type I hypersensitivity reactions is not shown to be effective and must not replace the prompt administration of epinephrine in the setting of anaphylaxis.

Additional targeted approaches for IgE-mediated disease include biologics that reduce IgE or type 2 inflammation. [[Omalizumab|Anti-IgE monoclonal antibodies]] lower free IgE and down-regulate [[FCER1|FcεRI]] on mast cells and basophils, decreasing effector cell sensitivity.<ref>{{Cite journal |last1=Guntern |first1=Pascal |last2=Eggel |first2=Alexander |date=October 2020 |title=Past, present, and future of anti-IgE biologics |journal=Allergy |volume=75 |issue=10 |pages=2491–2502 |doi=10.1111/all.14308 |issn=1398-9995 |pmc=7541678 |pmid=32249957}}</ref> Alternatively, blocking key type 2 cytokines such as [[Interleukin 4|IL-4]] and [[Interleukin 13|IL-13]] helps to control allergic inflammation.<ref>{{Cite journal |last1=Ogulur |first1=Ismail |last2=Mitamura |first2=Yasutaka |last3=Yazici |first3=Duygu |last4=Pat |first4=Yagiz |last5=Ardicli |first5=Sena |last6=Li |first6=Manru |last7=D'Avino |first7=Paolo |last8=Beha |first8=Carina |last9=Babayev |first9=Huseyn |last10=Zhao |first10=Bingjie |last11=Zeyneloglu |first11=Can |last12=Giannelli Viscardi |first12=Oliva |last13=Ardicli |first13=Ozge |last14=Kiykim |first14=Ayca |last15=Garcia-Sanchez |first15=Asuncion |date=2025-02-17 |title=Type 2 immunity in allergic diseases |journal=Cellular & Molecular Immunology |language=en |volume=22 |issue=3 |pages=211–242 |doi=10.1038/s41423-025-01261-2 |issn=2042-0226 |pmc=11868591 |pmid=39962262}}</ref> [[Interleukin 5|IL-5]] blockade has also been used to eliminate eosinophils from the body to help control these inflammatory responses.<ref>{{Cite journal |last1=Jacobsen |first1=Elizabeth A. |last2=Jackson |first2=David J. |last3=Heffler |first3=Enrico |last4=Mathur |first4=Sameer K. |last5=Bredenoord |first5=Albert J. |last6=Pavord |first6=Ian D. |last7=Akuthota |first7=Praveen |last8=Roufosse |first8=Florence |last9=Rothenberg |first9=Marc E. |date=2021-04-26 |title=Eosinophil Knockout Humans: Uncovering the Role of Eosinophils Through Eosinophil-Directed Biological Therapies |journal=Annual Review of Immunology |language=en |volume=39 |issue=1 |pages=719–757 |doi=10.1146/annurev-immunol-093019-125918 |issn=0732-0582 |pmc=8317994 |pmid=33646859}}</ref> In cases refractory to IL-4 and IL-13 blockade, upstream targeting of other cytokines like [[Thymic stromal lymphopoietin|TSLP]] can be effective.<ref>{{Cite journal |last1=Menzies-Gow |first1=Andrew |last2=Corren |first2=Jonathan |last3=Bourdin |first3=Arnaud |last4=Chupp |first4=Geoffrey |last5=Israel |first5=Elliot |last6=Wechsler |first6=Michael E. |last7=Brightling |first7=Christopher E. |last8=Griffiths |first8=Janet M. |last9=Hellqvist |first9=Åsa |last10=Bowen |first10=Karin |last11=Kaur |first11=Primal |last12=Almqvist |first12=Gun |last13=Ponnarambil |first13=Sandhia |last14=Colice |first14=Gene |date=2021-05-13 |title=Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma |url=http://www.nejm.org/doi/10.1056/NEJMoa2034975 |journal=New England Journal of Medicine |language=en |volume=384 |issue=19 |pages=1800–1809 |doi=10.1056/NEJMoa2034975 |pmid=33979488 |issn=0028-4793}}</ref> Leukotriene-pathway inhibitors ([[Leukotriene receptor antagonists|cysteinyl-leukotriene receptor antagonists]] or [[5-lipoxygenase inhibitors]]) are adjuncts for airway-predominant disease.<ref>{{Cite journal |last1=Côté |first1=Andreanne |last2=Russell |first2=Richard J. |last3=Boulet |first3=Louis-Philippe |last4=Gibson |first4=Peter G. |last5=Lai |first5=Kefang |last6=Irwin |first6=Richard S. |last7=Brightling |first7=Christopher E. |last8=Altman |first8=Kenneth W. |last9=Azoulay |first9=Elie |last10=Barker |first10=Alan F. |last11=Blackhall |first11=Fiona |last12=Bolser |first12=Donald C. |last13=Birring |first13=Surinder S. |last14=Braman |first14=Sidney S. |last15=Brightling |first15=Christopher |date=July 2020 |title=Managing Chronic Cough Due to Asthma and NAEB in Adults and Adolescents |url=https://linkinghub.elsevier.com/retrieve/pii/S0012369220300453 |journal=Chest |language=en |volume=158 |issue=1 |pages=68–96 |doi=10.1016/j.chest.2019.12.021|url-access=subscription }}</ref> For indispensable medications that elicit IgE-mediated reactions, rapid drug desensitization protocols can transiently induce mast-cell hyporesponsiveness, with protection persisting only while dosing continues.<ref>{{Cite journal |last=Castells |first=Mariana |date=August 2009 |title=Rapid Desensitization for Hypersensitivity Reactions to Medications |url=https://linkinghub.elsevier.com/retrieve/pii/S0889856109000356 |journal=Immunology and Allergy Clinics of North America |language=en |volume=29 |issue=3 |pages=585–606 |doi=10.1016/j.iac.2009.04.012 |pmid=19563999 |url-access=subscription }}</ref> Despite the central role of mast cells in the pathogenesis of type I hypersensitivity, [[mast cell stabilizer]]s are generally used only in mast cell activation syndromes (except for [[allergic conjunctivitis]]).

Type I hypersensitivity reactions are often amenable to [[Allergen immunotherapy|desensitization]] (allergen immunotherapy).<ref>{{Cite journal |last1=Alvaro-Lozano |first1=Montserrat |last2=Akdis |first2=Cezmi A. |last3=Akdis |first3=Mubeccel |last4=Alviani |first4=Cherry |last5=Angier |first5=Elisabeth |last6=Arasi |first6=Stefania |last7=Arzt-Gradwohl |first7=Lisa |last8=Barber |first8=Domingo |last9=Bazire |first9=Raphaëlle |last10=Cavkaytar |first10=Ozlem |last11=Comberiati |first11=Pasquale |last12=Dramburg |first12=Stephanie |last13=Durham |first13=Stephen R. |last14=Eifan |first14=Aarif O. |last15=Forchert |first15=Leandra |date=May 2020 |title=EAACI Allergen Immunotherapy User's Guide |journal=Pediatric Allergy and Immunology: Official Publication of the European Society of Pediatric Allergy and Immunology |volume=31 Suppl 25 |issue=Suppl 25 |pages=1–101 |doi=10.1111/pai.13189 |issn=1399-3038 |pmc=7317851 |pmid=32436290}}</ref> The basic principle of allergen immunotherapy involves exposing the patient to gradually escalating doses of allergen, sometimes with and sometimes without an [[Immunologic adjuvant|adjuvant]]. The specific form of immunotherapy (e.g., sublingual vs subcutaneous) depends on the nature of the allergen as well as patient characteristics. As successive exposure to the allergen occurs, the patient begins to develop IgG1 and IgG4 antibodies that compete with IgE for binding and inhibit IgE signaling, as well as develop [[regulatory T cell]]s that help to promote tolerance to the allergen.<ref>{{Cite journal |last1=Shamji |first1=Mohamed H. |last2=Sharif |first2=Hanisah |last3=Layhadi |first3=Janice A. |last4=Zhu |first4=Rongfei |last5=Kishore |first5=Uday |last6=Renz |first6=Harald |date=2022-03-01 |title=Diverse immune mechanisms of allergen immunotherapy for allergic rhinitis with and without asthma |url=https://www.sciencedirect.com/science/article/pii/S0091674922000860 |journal=Journal of Allergy and Clinical Immunology |volume=149 |issue=3 |pages=791–801 |doi=10.1016/j.jaci.2022.01.016 |pmid=35093483 |issn=0091-6749}}</ref> However, maintenance of tolerance often requires regular re-exposure to the allergen. It is also not unusual for type I hypersensitivities to fade over time, particularly in children. For example, most patients with genuine penicillin allergy lose their reactivity within 10 years.<ref>{{Cite journal |author1=Joint Task Force on Practice Parameters |last2=American Academy Of Allergy |first2=Asthma Immunology |last3=American College Of Allergy |first3=Asthma Immunology |last4=Joint Council Of Allergy |first4=Asthma Immunology |date=2010-10-01 |title=Drug Allergy: An Updated Practice Parameter |url=https://www.annallergy.org/article/S1081-1206(10)00734-9/abstract |journal=Annals of Allergy, Asthma & Immunology |language=English |volume=105 |issue=4 |pages=259–273.e78 |doi=10.1016/j.anai.2010.08.002 |pmid=20934625 |issn=1081-1206}}</ref> Nonetheless, some are persistent, particularly in the absence of desensitization therapy (such as peanut allergy).<ref>{{Cite journal |last1=Skolnick |first1=Helen S. |last2=Conover-Walker |first2=Mary Kay |last3=Koerner |first3=Celide Barnes |last4=Sampson |first4=Hugh A. |last5=Burks |first5=Wesley |last6=Wood |first6=Robert A. |date=2001-02-01 |title=The natural history of peanut allergy |url=https://www.jacionline.org/article/S0091-6749(01)48941-X/fulltext |journal=Journal of Allergy and Clinical Immunology |language=English |volume=107 |issue=2 |pages=367–374 |doi=10.1067/mai.2001.112129 |issn=0091-6749 |pmid=11174206}}</ref>

Depending on the severity of the type I hypersensitivity, it may also be important to avoid exposure to the allergen completely, if possible. Repeated exposures to the allergen may lead to increases in IgE levels and more intense activation of mast cells and basophils. It is unclear why allergen immunotherapy is able to induce tolerance whereas re-exposure to the allergen under native conditions typically exacerbates type I hypersensitivity, but it is likely a combination of the route of exposure and dose of the allergen, as well as the overall immunological context through which it is encountered.

== Type II hypersensitivity ==

{{Main|Type II hypersensitivity}}

Type II hypersensitivity reaction refers to a reaction in which antibodies (classically IgG or IgM) are directed against cellular or extracellular matrix antigens with the resultant cellular destruction, functional loss, or damage to tissues. The antigens may occur normally within the body (intrinsic antigens) or may be introduced from the environment (extrinsic antigens).<ref name=":6">{{Cite book |title=Robbins & Cotran pathologic basis of disease |date=2021 |publisher=Elsevier |isbn=978-0-323-53113-9 |editor-last=Kumar |editor-first=Vinay |edition=Tenth |location=Philadelphia, PA |editor-last2=Abbas |editor-first2=Abul K. |editor-last3=Aster |editor-first3=Jon C. |editor-last4=Turner |editor-first4=Jerrold R. |editor-last5=Perkins |editor-first5=James Alfred |editor-last6=Robbins |editor-first6=Stanley L. |editor-last7=Cotran |editor-first7=Ramzi S.}}</ref><ref name=":3">{{Cite book |last1=Murphy |first1=Kenneth M. |title=Janeway's immunobiology |last2=Weaver |first2=Casey |date=2017 |publisher=GS, Garland Science, Taylor & Francis Group |others=Charles A. Janeway, Allan Mowat, Leslie J. Berg, David D. Chaplin, Paul Travers, Mark Walport |isbn=978-0-8153-4551-0 |edition=9th |location=New York London}}</ref> [[File:Type II hypersensitivity.webm|thumb|Type II hypersensitivity]]
Physiological dysfunction occurs via some combination of:
* Altered receptor signaling due to antibody binding. The signaling may be enhanced by antibody binding (as in [[Graves' disease|Graves's disease]]) or inhibited (as in [[myasthenia gravis]]).
* Activation of the complement system via the classical pathway, causing formation of the [[Complement membrane attack complex|membrane attack complex]], [[anaphylatoxin]] production, and [[opsonization]].
* Fc-mediated effector functions (e.g., [[antibody-dependent cellular cytotoxicity]], [[Opsonin|opsonization and phagocytosis]], cytokine secretion, [[degranulation]], [[reactive oxygen species]] production, increased expression of [[Co-stimulation|costimulatory]] ligands and [[MHC class II]]).<ref name=":4">{{Cite journal |last1=Bournazos |first1=Stylianos |last2=Wang |first2=Taia T. |last3=Dahan |first3=Rony |last4=Maamary |first4=Jad |last5=Ravetch |first5=Jeffrey V. |date=2017-04-26 |title=Signaling by Antibodies: Recent Progress |journal=Annual Review of Immunology |language=en |volume=35 |issue=1 |pages=285–311 |doi=10.1146/annurev-immunol-051116-052433 |issn=0732-0582 |pmc=5613280 |pmid=28446061}}</ref><ref name=":5">{{Cite journal |last1=Pincetic |first1=Andrew |last2=Bournazos |first2=Stylianos |last3=DiLillo |first3=David J |last4=Maamary |first4=Jad |last5=Wang |first5=Taia T |last6=Dahan |first6=Rony |last7=Fiebiger |first7=Benjamin-Maximillian |last8=Ravetch |first8=Jeffrey V |date=August 2014 |title=Type I and type II Fc receptors regulate innate and adaptive immunity |journal=Nature Immunology |language=en |volume=15 |issue=8 |pages=707–716 |doi=10.1038/ni.2939 |issn=1529-2908 |pmc=7430760 |pmid=25045879}}</ref>
IgA may also play a role in type II hypersensitivity reactions as in [[Linear IgA bullous dermatosis|linear IgA disease]] or [[IgA pemphigus]], though it is not classically included in the definition of type II hypersensitivities.

The onset of symptoms following exposure is usually hours to days, but the conditions mediated by type II hypersensitivity are often chronic.

Type II hypersensitivities have multiple overlapping features with type III hypersensitivities. The principal distinctions lie in:

# Where the immune complex forms:
## soluble phase corresponds to type III.
## matrix or membrane-bound corresponds to type II.
# Where the tissue damage occurs:
## local to the antigen corresponds to type II.
## distally as in through deposition into the vasculature, glomeruli, or synovium, corresponds to type III.

[[Autoimmune hemolytic anemia]]s are classic examples of type II hypersensitivities. In this case, antibodies cause lysis of red blood cells by binding to their surface and initiating the canonical type II hypersensitivity mechanisms. These can be diagnosed via the [[Coombs test]]. In the direct Coombs test, a patient's blood is taken and incubated with antihuman antibodies (the Coombs reagent). The result is positive (indicating binding of antibodies in the patient to red blood cells) when [[Agglutination|clumping of the red blood cells]] occurs. The indirect Coombs test is similar, but uses the serum of the donor rather than their whole blood and uses non-donor red blood cells with the Coombs reagent. As with the direct Coombs test, the result is positive when clumping of red blood cells occurs.

The management of type II hypersensitivities is heterogeneous and depends on the specific hypersensitivity.

== Type III hypersensitivity ==

{{Main|Type III hypersensitivity}}

[[File:Type III hypersensivity.webm|thumb|Type III hypersensitivity]]
Type III hypersensitivities occur in response to soluble antigens. These antigens are recognized by antibodies and form lattices of antigen and antibody (sometimes incorporating complement) known as immune complexes. As these circulate, the immune complexes may become deposited in various tissues, wherein they mediate tissue damage through mechanisms that greatly overlap with type II hypersensitivity, though classically there is a greater emphasis on the role of [[neutrophil]]s as drivers of inflammation in type III hypersensitivity. Textbooks often underemphasize the role of [[Fc receptor|FcγR]] signaling in the clinical manifestations of type III hypersensitivities,<ref>{{Cite journal |last1=Sylvestre |first1=Diana L. |last2=Ravetch |first2=Jeffrey V. |date=1994-08-19 |title=Fc Receptors Initiate the Arthus Reaction: Redefining the Inflammatory Cascade |url=https://www.science.org/doi/10.1126/science.8066448 |journal=Science |language=en |volume=265 |issue=5175 |pages=1095–1098 |doi=10.1126/science.8066448 |pmid=8066448 |bibcode=1994Sci...265.1095S |issn=0036-8075|url-access=subscription }}</ref> instead focusing on complement. However, at least for the Arthus reaction, FcγR's appear to be much more important for disease than complement. Nonetheless, there is reciprocal regulation of these pathways as the expression of activating FcγRs is shown to be increased by [[C5a receptor]] signaling.<ref>{{Cite journal |last1=Shushakova |first1=Nelli |last2=Skokowa |first2=Julia |last3=Schulman |first3=Jurriaan |last4=Baumann |first4=Ulrich |last5=Zwirner |first5=Jörg |last6=Schmidt |first6=Reinhold E. |last7=Gessner |first7=J. Engelbert |date=2002-12-15 |title=C5a anaphylatoxin is a major regulator of activating versus inhibitory FcγRs in immune complex–induced lung disease |journal=Journal of Clinical Investigation |language=en |volume=110 |issue=12 |pages=1823–1830 |doi=10.1172/JCI16577 |pmid=12488432 |pmc=151656 |issn=0021-9738}}</ref> Additionally, there are instances in which complement does appear to be key to the pathogenesis of type III hypersensitivity. For example, the first [[Respiratory syncytial virus vaccine|RSV vaccines]] attempted (which were never licensed), comprising formalin-inactivated RSV precipitated on [[Vaccine adjuvant|alum]], caused a heightened risk of hospitalization upon RSV infection in children ([[Vaccine-associated enhanced respiratory disease|vaccine-associated enhanced respiratory disease, VAERD]]), in part through mechanisms that are consistent with type III hypersensitivity.<ref>{{Cite journal |last=Acosta |first=Patricio L. |last2=Caballero |first2=Mauricio T. |last3=Polack |first3=Fernando P. |date=2016-03-07 |title=Brief History and Characterization of Enhanced Respiratory Syncytial Virus Disease |url=https://journals.asm.org/doi/10.1128/cvi.00609-15 |journal=Clinical and Vaccine Immunology |volume=23 |issue=3 |pages=189–195 |doi=10.1128/CVI.00609-15|doi-access=free }}</ref> However, complement deficiency is protective against VAERD.<ref>{{Cite journal |last=Polack |first=Fernando P. |last2=Teng |first2=Michael N. |last3=L.Collins |first3=Peter |last4=Prince |first4=Gregory A. |last5=Exner |first5=Marcus |last6=Regele |first6=Heinz |last7=Lirman |first7=Dario D. |last8=Rabold |first8=Richard |last9=Hoffman |first9=Scott J. |last10=Karp |first10=Christopher L. |last11=Kleeberger |first11=Steven R. |last12=Wills-Karp |first12=Marsha |last13=Karron |first13=Ruth A. |date=2002-09-16 |title=A Role for Immune Complexes in Enhanced Respiratory Syncytial Virus Disease |url=https://rupress.org/jem/article/196/6/859/39497/A-Role-for-Immune-Complexes-in-Enhanced |journal=The Journal of Experimental Medicine |language=en |volume=196 |issue=6 |pages=859–865 |doi=10.1084/jem.20020781 |issn=1540-9538 |pmc=2194058 |pmid=12235218}}</ref> Similar findings have been reported with atypical [[measles]] syndrome, associated with measles infection following vaccination with the killed measles vaccine (which was withdrawn from market in 1968).<ref>{{Cite journal |last=Polack |first=Fernando P |last2=Hoffman |first2=Scott J |last3=Crujeiras |first3=Gonzalo |last4=Griffin |first4=Diane E |date=2003-09-01 |title=A role for nonprotective complement-fixing antibodies with low avidity for measles virus in atypical measles |url=https://www.nature.com/articles/nm918 |journal=Nature Medicine |language=en |volume=9 |issue=9 |pages=1209–1213 |doi=10.1038/nm918 |issn=1078-8956|url-access=subscription }}</ref>

In general, type III reactions occur within a matter of hours of exposure to the antigen, unless it is the first exposure in which case there is a delay to formation of antibodies (as in serum sickness) to about 7–14 days post-exposure, with more rapid onset with successive re-exposures.<ref name=":3" />

While there are assays that detect immune complexes, most hospitals do not have them and so their usefulness is limited. Complement levels can often provide a hint that type III hypersensitivity is occurring: a drop in [[Complement component 4|C4]] and [[Complement component 3|C3]] implies [[Classical complement pathway|classical pathway]] activation, often associated with [[Lupus|SLE]]. A drop in C3, [[Complement factor B|factor B]], or [[properdin]] suggests [[Alternative complement pathway|alternative pathway]] activation, often associated with [[membranoproliferative glomerulonephritis]].<ref name=":0" />

The management of type III hypersensitivities is heterogeneous and depends on the specific hypersensitivity.

=== Molecular mechanisms ===
The size of the immune complexes is an important determinant of the clinical manifestations of disease. Immune complex size depends on the amount and ratio of antibody to antigen, with the largest ones forming at intermediate quantities of both.<ref>{{Cite journal |last=Lu |first=Lenette L. |last2=Suscovich |first2=Todd J. |last3=Fortune |first3=Sarah M. |last4=Alter |first4=Galit |date=January 2018 |title=Beyond binding: antibody effector functions in infectious diseases |url=https://www.nature.com/articles/nri.2017.106 |journal=Nature Reviews Immunology |language=en |volume=18 |issue=1 |pages=46–61 |doi=10.1038/nri.2017.106 |issn=1474-1733 |pmc=6369690 |pmid=29063907}}</ref> Large immune complexes are more readily phagocytosed by [[Kupffer cell]]s and red pulp macrophages, whereas small ones are more readily deposited into tissues.<ref name=":0" /> Immune complexes formed at moderate excess antigen levels (slightly more than the level that maximizes the size of complexes) are thought to be the most pathogenic because they are harder to clear than large complexes, remain in the circulation for longer, and can readily fix complement (which small immune complexes do not do as effectively). The glomerular and skin basement membranes' negative charge can promote deposition of positively charged immune complexes into these sites. In some cases, positively charged antigens may first deposit into the basement membrane of glomeruli before immune complexes form (though canonically in type III hypersensitivity immune complex formation happens first). Antigen and antibody structure are also key determinants of immune complex size. For example, immune complexes cannot form when the antibodies all bind the same exact epitope or overlapping epitopes, unless the epitope in question occurs multiple times on the surface of the antigen (as in a multivalent antigen).<ref name=":0" /> In an immune response, many different antibodies may be elicited by the same antigen and these may not overlap in their epitopes, making immune complex formation occur more readily. Antibody binding must be at least bivalent (i.e., both antibody paratopes have to be occupied) and antigen must be multivalent for there to be any possibility of immune complex formation. [[Rheumatoid factor]] can increase the size of immune complexes and often arises transiently in the course of immune responses, amplifying antibody signaling (it does not automatically indicate rheumatoid arthritis, though it is rarely found under basal conditions in healthy people).<ref>{{Cite journal |last=Newkirk |first=Marianna M. |date=July 2002 |title=Rheumatoid Factors: Host Resistance or Autoimmunity? |url=https://linkinghub.elsevier.com/retrieve/pii/S1521661602952101 |journal=Clinical Immunology |language=en |volume=104 |issue=1 |pages=1–13 |doi=10.1006/clim.2002.5210 |pmid=12139942 |url-access=subscription }}</ref>

The biological activity of immune complexes also depends on the antibody isotype and subclass.<ref>{{Cite journal |last1=Nimmerjahn |first1=Falk |last2=Ravetch |first2=Jeffrey V. |date=2005-12-02 |title=Divergent Immunoglobulin G Subclass Activity Through Selective Fc Receptor Binding |url=https://www.science.org/doi/10.1126/science.1118948 |journal=Science |language=en |volume=310 |issue=5753 |pages=1510–1512 |doi=10.1126/science.1118948 |pmid=16322460 |bibcode=2005Sci...310.1510N |issn=0036-8075|url-access=subscription }}</ref> [[IgG4]] for example is not as efficient at forming immune complexes because it readily undergoes Fab arm exchange and thus behaves as though it has only one binding site (functional monovalency), and is a poor activator of complement.<ref>{{Cite journal |last1=Rispens |first1=Theo |last2=Ooijevaar-de Heer |first2=Pleuni |last3=Bende |first3=Onno |last4=Aalberse |first4=Rob C. |date=2011-07-06 |title=Mechanism of Immunoglobulin G4 Fab-arm Exchange |journal=Journal of the American Chemical Society |volume=133 |issue=26 |pages=10302–10311 |doi=10.1021/ja203638y |pmid=21627172 |bibcode=2011JAChS.13310302R |issn=0002-7863}}</ref><ref>{{Cite journal |last1=Rispens |first1=Theo |last2=Huijbers |first2=Maartje G. |date=November 2023 |title=The unique properties of IgG4 and its roles in health and disease |journal=Nature Reviews Immunology |language=en |volume=23 |issue=11 |pages=763–778 |doi=10.1038/s41577-023-00871-z |issn=1474-1733 |pmc=10123589 |pmid=37095254}}</ref> In contrast, IgM is among the most potent activators of the classical pathway of complement activation of all the isotypes and readily forms immune complexes because it has 10 binding sites in its soluble pentameric form. Antibody classes and subclasses also differ in their ability to engage Fc receptors, which in turn influences the effector functions elicited by immune complexes.

Similarly, the glycosylation of IgG antibodies is a key modifier of effector functions, with [[Fucose|afucosylation]] of the Fc glycan resulting in markedly enhanced affinity for CD16 and consequently enhanced inflammation, whereas [[sialylation]] of the Fc glycan causes IgG to change conformation and enables binding to type II FcγRs, which have anti-inflammatory effects.<ref name=":4" /><ref name=":5" /> [[Galactose|Galactosylation]] of the Fc glycan promotes oligomerization of IgG, facilitating efficient complement activation.<ref>{{Cite journal |last1=van Osch |first1=Thijs L J |last2=Nouta |first2=Jan |last3=Derksen |first3=Ninotska I L |last4=van Mierlo |first4=Gerard |last5=van der Schoot |first5=C Ellen |last6=Wuhrer |first6=Manfred |last7=Rispens |first7=Theo |last8=Vidarsson |first8=Gestur |date=2021-09-15 |title=Fc Galactosylation Promotes Hexamerization of Human IgG1, Leading to Enhanced Classical Complement Activation |journal=The Journal of Immunology |language=en |volume=207 |issue=6 |pages=1545–1554 |doi=10.4049/jimmunol.2100399 |issn=0022-1767 |pmc=8428746 |pmid=34408013}}</ref>

== Type IV hypersensitivity ==

{{Main|Type IV hypersensitivity}}

[[File:Type IV hypersensitivity.webm|thumb|Type IV hypersensitivity]]
Type IV hypersensitivity reactions are classically described as delayed-type hypersensitivities (DTH) because onset of symptoms following exposure takes 48–72 hours.<ref name=":3" /><ref name=":0" /><ref name=":6" /> Formally, however, the term DTH is most tightly associated with [[Mantoux test|tuberculin skin testing]] and reflects type IVa hypersensitivity (see below). The 48- to 72-hour delay reflects the time required for: (1) antigen-specific memory T cells to encounter antigen and become activated, (2) these cells to proliferate locally, and (3) recruitment of effector cells to the site of exposure.

The critical feature of type IV hypersensitivity reactions is their dependency on T cells (type I, II, and III are dependent on antibodies). They may be initiated only after an antigen has been presented on class II MHC proteins and recognized by CD4 T cells. Initially, there is a sensitization event that elicits T cell responses against the antigen (not IgE in this case), which results in memory CD4 T cells. Re-exposure results in a more rapid response from these cells.

CD8 T cells may also play a role in type IV hypersensitivities (particularly type IVc), but they are dependent on CD4 T cells for activation, hence induction of CD4 T cell responses is the essential aspect of type IV hypersensitivities.<ref>{{Cite journal |last1=Laidlaw |first1=Brian J. |last2=Craft |first2=Joseph E. |last3=Kaech |first3=Susan M. |date=February 2016 |title=The multifaceted role of CD4(+) T cells in CD8(+) T cell memory |journal=Nature Reviews. Immunology |volume=16 |issue=2 |pages=102–111 |doi=10.1038/nri.2015.10 |issn=1474-1741 |pmc=4860014 |pmid=26781939}}</ref> Limited helper-independent CD8 T cell priming can occur under strong innate adjuvanticity, but helper T cell-dependent licensing is the prevailing mechanism in classic type IV disease.

The specific nature of the hypersensitivity reaction depends on the characteristics of the T cell response to the antigen:<ref name=":7">{{Cite journal |last1=Uzzaman |first1=Ashraf |last2=Cho |first2=Seong H. |date=2012 |title=Chapter 28: Classification of hypersensitivity reactions |journal=Allergy and Asthma Proceedings |volume=33 Suppl 1 |issue=3 |pages=96–99 |doi=10.2500/aap.2012.33.3561 |issn=1539-6304 |pmid=22794701}}</ref>

* '''Type IVa (Th1/macrophage-predominant):''' Th1 cells produce IFN-γ and TNF-α to activate macrophages, leading to granuloma formation in persistent responses. ''Examples:'' tuberculin skin test; granulomatous inflammation to mycobacterial antigens; allergic contact dermatitis.
* '''Type IVb (Th2/eosinophil-predominant):''' Th2 cells produce IL-4/IL-5/IL-13 to induce eosinophilic inflammation. ''Examples:'' drug reaction with eosinophilia and systemic symptoms (DRESS); some chronic eczematous drug eruptions.
* '''Type IVc (cytotoxic T-cell-predominant):''' CD8 T cells (typically activated by Th1 cells in addition to professional antigen presenting cells) release perforin, granzyme B, and Fas-FasL interactions to cause direct cell death. ''Examples:'' Stevens–Johnson syndrome/toxic epidermal necrolysis, fixed drug eruption, acute T-cell–mediated graft rejection (graft rejection often has type IVa features as well).
* '''Type IVd (T-cell/neutrophil-predominant):''' T-cell–derived CXCL8 (IL-8) and GM-CSF recruit/activate neutrophils. ''Examples:'' acute generalized exanthematous pustulosis; pustular psoriasis.

Many DTH reactions are [[hapten]]-dependent, such as for various metal allergies (nickel, chromium). The hapten modifies or associates with a carrier to generate neo-epitopes (often covalent for classic haptens such as many drugs; metal ions can act via coordination with peptides/MHC rather than strictly covalent binding). Small molecule drugs can also function as haptens e.g., penicillin (penicillin may elicit all 4 types of hypersensitivity reactions defined by Gell and Coombs).<ref>{{Cite journal |last1=Green |first1=Estelle A. |last2=Fogarty |first2=Kelan |last3=Ishmael |first3=Faoud T. |date=June 2023 |title=Penicillin Allergy: Mechanisms, Diagnosis, and Management |journal=Primary Care |volume=50 |issue=2 |pages=221–235 |doi=10.1016/j.pop.2022.11.002 |issn=1558-299X |pmid=37105603}}</ref>

Diagnosis of Type IV hypersensitivities varies by subtype. Contact dermatitis (IVa) is diagnosed via patch testing, where suspected allergens are applied to the skin and read at 48–72 hours. Drug-related Type IV reactions are typically diagnosed clinically, as provocative testing is dangerous. The tuberculin skin test itself is a diagnostic use of Type IV hypersensitivity.

In contrast with type I hypersensitivities, type IV hypersensitivities are generally not amenable to desensitization, especially toxic epidermal necrolysis or Stevens-Johnson syndrome wherein re-exposure can be fatal. Prevention emphasizes avoidance of the offending allergen.

Treatment involves removing the antigen when possible and immunosuppression appropriate to severity: topical corticosteroids for contact dermatitis, systemic corticosteroids for DRESS, and supportive care for SJS/TEN. Unlike Type I reactions, antihistamines may provide limited symptomatic relief (e.g., [[Itch|pruritus]]) but are not disease-modifying; epinephrine has no role.

Conditions that impair T cell responses can reduce type IV hypersensitivity reactions, although there are important nuances (see ''Effects of Immunodeficiencies on Hypersensitivity Reactions'').

== Effects of Immunodeficiencies on Hypersensitivity Reactions ==
Intuitively, it might be expected that because hypersensitivities represent inappropriate responses of the immune system, immunodeficient states should lend themselves to protection against such reactions or less severe reactions. However, several clinically important paradoxes demonstrate that this is not necessarily the case.

* '''[[Psoriasis]]:''' Psoriasis pathogenesis shares features with type IV hypersensitivity (in particular, type IVd for pustular psoriasis<ref name=":7" />) with a clear [[T helper 17 cell|Th17 cell]]-driven phenotype,<ref>{{Cite journal |last1=Armstrong |first1=April W. |last2=Blauvelt |first2=Andrew |last3=Callis Duffin |first3=Kristina |last4=Huang |first4=Yu-Huei |last5=Savage |first5=Laura J. |last6=Guo |first6=Lily |last7=Merola |first7=Joseph F. |date=2025-06-26 |title=Psoriasis |url=https://www.nature.com/articles/s41572-025-00630-5 |journal=Nature Reviews Disease Primers |language=en |volume=11 |issue=1 |article-number=45 |doi=10.1038/s41572-025-00630-5 |pmid=40571687 |issn=2056-676X|url-access=subscription }}</ref> but may drastically worsen in [[HIV]] infection because [[regulatory T cell]]s are depleted by HIV and because the loss of T cells can contribute to skin dysbiosis that promotes inflammation.<ref>{{Cite journal |last1=Gudjonsson |first1=J. E. |last2=Johnston |first2=A. |last3=Sigmundsdottir |first3=H. |last4=Valdimarsson |first4=H. |date=January 2004 |title=Immunopathogenic mechanisms in psoriasis |journal=Clinical and Experimental Immunology |volume=135 |issue=1 |pages=1–8 |doi=10.1111/j.1365-2249.2004.02310.x |issn=0009-9104 |pmc=1808928 |pmid=14678257}}</ref><ref>{{Cite journal |last1=Motswaledi |first1=Mojakgomo Hendrick |last2=Visser |first2=Willie |date=April 2014 |title=The spectrum of HIV-associated infective and inflammatory dermatoses in pigmented skin |journal=Dermatologic Clinics |volume=32 |issue=2 |pages=211–225 |doi=10.1016/j.det.2013.12.006 |issn=1558-0520 |pmid=24680007}}</ref><ref>{{Cite journal |last=Namazi |first=M. R. |date=February 2004 |title=Paradoxical exacerbation of psoriasis in AIDS: proposed explanations including the potential roles of substance P and gram-negative bacteria |journal=Autoimmunity |volume=37 |issue=1 |pages=67–71 |doi=10.1080/08916930310001637986 |issn=0891-6934 |pmid=15115314}}</ref> Psoriasis may even be the initial presentation for [[acute retroviral syndrome]]. 
* '''[[Complement deficiency]]:''' Despite the centrality of complement in type III hypersensitivities such as [[lupus]], complement deficiencies (particularly in the classical pathway) are a major risk factor for developing systemic lupus erythematosus.<ref>{{Cite journal |last1=Leffler |first1=Jonatan |last2=Bengtsson |first2=Anders A |last3=Blom |first3=Anna M |date=September 2014 |title=The complement system in systemic lupus erythematosus: an update |url=https://linkinghub.elsevier.com/retrieve/pii/S0003496724098819 |journal=Annals of the Rheumatic Diseases |language=en |volume=73 |issue=9 |pages=1601–1606 |doi=10.1136/annrheumdis-2014-205287 |pmid=24845390 }}</ref> This is believed to be due to the fact that in the absence of complement components, immune complexes persist for longer and can promote destructive inflammation in tissues, helping to enable autoantibody responses. 
* '''[[Selective immunoglobulin A deficiency|IgA deficiency]]''' and [[Coeliac disease|'''Celiac disease''']]: Celiac disease (a predominantly type IV hypersensitivity) is another example of such a paradox: despite IgA against [[tissue transglutaminase]] and [[gliadin]] being part of the diagnostic testing for celiac disease, [[IgA deficiency]] markedly increases the risk of celiac disease development, and so total IgA titers should be obtained in conjunction with other serologies to ensure negative results are true negatives.<ref>{{Cite journal |last1=Kumar |first1=V. |last2=Jarzabek-Chorzelska |first2=M. |last3=Sulej |first3=J. |last4=Karnewska |first4=Krystyna |last5=Farrell |first5=T. |last6=Jablonska |first6=S. |date=November 2002 |title=Celiac disease and immunoglobulin a deficiency: how effective are the serological methods of diagnosis? |journal=Clinical and Diagnostic Laboratory Immunology |volume=9 |issue=6 |pages=1295–1300 |doi=10.1128/cdli.9.6.1295-1300.2002 |issn=1071-412X |pmc=130112 |pmid=12414763}}</ref>
* '''[[Omenn syndrome]]''': Omenn syndrome is a form of [[severe combined immunodeficiency]] in which there is a near complete absence of B cells, limited oligoclonal [[Autoreactive lymphocyte|autoreactive]] T cells that produce [[type 2 cytokine]]s, and a tendency towards IgE production with [[eosinophilia]], causing a predisposition towards type I and type IVb (under EAACI 2023 taxonomies) hypersensitivities.<ref>{{Cite journal |last1=Villa |first1=Anna |last2=Notarangelo |first2=Luigi D. |last3=Roifman |first3=Chaim M. |date=2008-12-01 |title=Omenn syndrome: Inflammation in leaky severe combined immunodeficiency |url=https://www.jacionline.org/article/S0091-6749(08)01734-X/fulltext |journal=Journal of Allergy and Clinical Immunology |language=English |volume=122 |issue=6 |pages=1082–1086 |doi=10.1016/j.jaci.2008.09.037 |issn=0091-6749 |pmid=18992930}}</ref><ref>{{Cite journal |last1=Notarangelo |first1=Luigi D. |last2=Kim |first2=Min-Sung |last3=Walter |first3=Jolan E. |last4=Lee |first4=Yu Nee |date=April 2016 |title=Human RAG mutations: biochemistry and clinical implications |journal=Nature Reviews. Immunology |volume=16 |issue=4 |pages=234–246 |doi=10.1038/nri.2016.28 |issn=1474-1741 |pmc=5757527 |pmid=26996199}}</ref>

These paradoxes illustrate that hypersensitivity reactions reflect immune dysregulation rather than mere hyperreactivity. Loss of regulatory mechanisms, impaired clearance of antigens or immune complexes, and compensatory immune responses can all lead to hypersensitivity manifestations in immunodeficient states.

==References==
{{Reflist}}

== External links ==
{{Medical resources
|   DiseasesDB     = 28827
|   ICD10          = {{ICD10|T|78|4|t|66}}
|   ICD9           = {{ICD9|995.3}}
|   ICDO           =
|   OMIM           =
|   MedlinePlus    =
|   eMedicineSubj  =
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|   MeshID         = D006967
}}

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[[Category:Hypersensitivity| ]]
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[[Category:Effects of external causes]]

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