Types of Hypersensitivity Reaction

The hypersensitivity classification system used here was first described by Coombs and Gell (Fig. 25.1). The system
classifies the different types of hypersensitivity reaction by the types of immune response involved. Each type of
hypersensitivity reaction produces characteristic clinical disease whether the trigger is an environmental, infectious, or
self antigen. For example, in type III hypersensitivity, the clinical result is similar whether the antigen is streptococcus,
a drug, or an autoantigen, such as DNA.

F I G . 2 5 . 1 Coombs and Gell Classification of Hypersensitivity

Hypersensitivity reactions are reliant on the adaptive immune system. Previous exposure to antigen is required to
prime the adaptive immune response to produce IgE (type I), IgG (types II and III), or T cells (type IV). Because
previous exposure is required, hypersensitivity reactions do not take place when an individual is first exposed to
antigen. In each type of hypersensitivity reaction, the damage is caused by different aspects of the adaptive and
innate systems, each of which should now be familiar to you through discussion of their role in clearing infections.
Type I
Type I hypersensitivity is mediated through the degranulation of mast cells and eosinophils. The effects are felt within
minutes of exposure (Box 25.1). This type of hypersensitivity is sometimes referred to as immediate
hypersensitivity and is also known as allergy (see Chapter 26).
Type II
Type II hypersensitivity is caused by IgG reacting with antigen present on the surface of cells. The bound Ig then
interacts with complement or with Fc receptor on macrophages. These innate mechanisms then damage the target
cells using processes that may take several hours, as in the case of drug-induced hemolysis (Box 25.2).
Type III
Ig is also responsible for type III hypersensitivity. In this case, immune complexes of antigen and antibody form and
either cause damage at the site of production or circulate and cause damage elsewhere. Immune complexes take
some time to form and to initiate tissue damage. Poststreptococcal glomerulonephritis is a good example of immune
complex disease (Box 25.3 and see Chapter 29).
Contact dermatitis is an example of type IV delayed hypersensitivity. The skin lesions consist of T cells and
macrophages and develop 24 to 72 hours after exposure to the antigen. In this way, the lesions of contact dermatitis
are very similar to those
Type IV
The slowest form of hypersensitivity is that mediated by T cells (type IV hypersensitivity). This can take 2 to 3 days to
develop and is referred to as delayed hypersensitivity (Box 25.4 and Chapter 30).

Autoimmune diseases arise from an abnormal immune response of the body against substances and tissues
normally present in the body (autoimmunity). This may be restricted to certain organs (e.g. in autoimmune thyroiditis)
or involve a particular tissue in different places (e.g. Goodpasture's disease which may affect the basement
membrane in both the lung and the kidney). The treatment of autoimmune diseases is typically
with immunosuppressionmedication that decreases the immune response. A large number of autoimmune diseases
are recognized. A major understanding of the underlying pathophysiology of autoimmune diseases has been the
application of genome wide association scans that have identified a striking degree of genetic sharing among the
autoimmune diseases.[1]
Criteria
For a disease to be regarded as an autoimmune disease it needs to answer to Witebsky's postulates (first formulated
by Ernst Witebsky and colleagues in 1957 and modified in 1994): [2][3]

Direct evidence from transfer of pathogenic antibody or pathogenic T cells

Indirect evidence based on reproduction of the autoimmune disease in experimental animals

Circumstantial evidence from clinical clues

Genetic architecture clustering with other autoimmune diseases

Effects
It has been estimated that autoimmune diseases are among the ten leading causes of death among women in all age
groups up to 65 years.[4]
A substantial minority of the population suffers from these diseases, which are often chronic, debilitating, and lifethreatening. There are more than eighty illnesses caused by autoimmunity. [5]
Classification
It is possible to classify autoimmune diseases by corresponding type of hypersensitivity: type II, type III, or type IV. (No
type of autoimmune disease mimics type I hypersensitivity.)[6]
There is continuing debate about when a disease should be considered autoimmune, leading to different criteria such
as Witebsky's postulates.
This is an incomplete list that may never be able to satisfy particular standards for completeness. You can help
by expanding it with entries that are reliably sourced.

Name:
Acute disseminated
encephalomyelitis (ADEM)

Accepted/
suspected

Hypersensitivit
y
I, II, III, IV

Autoantibody

Accepted[7]

Addison's disease

21 hydroxylase
IGHM; IGLL1: CD79A; CD7
9B; BLNK; LRRC8A

Agammaglobulinemia
Alopecia areata

Accepted[8][9]

T-cells

Amyotrophic lateral
sclerosis(Also Lou Gehrig's
disease;Motor Neuron
Disease)
Ankylosing Spondylitis

Antiphospholipid syndrome

Notes

VCP, ATXN2, OPTN, FIG4, T

ARDBP, ANG,VAPB, FUS, S
ETX, ALS2, SOD1
Suspected[10]

CD8; HLA-B27

[11]

anti-cardiolipin;anti pyruvate
dehydrogenase; 2
HLA-DR7, HLA-B8, HLAglycoprotein
DR2, HLA-DR3
I; phosphatidylserine; anti
apoH; Annexin A5

Accepted[7]

Antisynthetase syndrome
Atopic allergy

Atopic dermatitis

Autoimmune aplastic
anemia
Autoimmune
cardiomyopathy

Accepted

Autoimmune enteropathy
Autoimmune hemolytic
anemia

Accepted

Autoimmune hepatitis

Accepted

Autoimmune inner ear

disease

Accepted

Autoimmune
lymphoproliferative
syndrome

Accepted

Autoimmune peripheral
neuropathy

Accepted

Autoimmune pancreatitis

Accepted

Autoimmune
polyendocrine syndrome

Accepted

Autoimmune progesterone
dermatitis

Accepted

Autoimmune
thrombocytopenic purpura

Accepted

Autoimmune urticaria

Accepted

Autoimmune uveitis

Accepted

Balo disease/Balo

II

cell-mediated

complement activation
anti-mitochondrial
antibodies; ANA; anti-smooth
muscle antibodies, LKM-1;
soluble liver antigen
[12]

TNFRSF6; defective FasCD95 apoptosis

ANA; anti-lactoferrin
antibodiesanti-carbonic
anhydrase
antibodies; rheumatoid factor
Unknown or
multiple

APS-1 see Addison's

disease

anti gpIIb-IIIa or 1b-IX

[13]

HLAB-27?

Name:

Accepted/
suspected

Hypersensitivit
y
I, II, III, IV

Autoantibody

Notes

concentric sclerosis

Behet's disease

immune-mediated
systemic vasculitis;
linkage to HLA-B51 (HLAB27); very different
manifestations with ulcers
as common symptom; also
called Morbus
Adamandiades-Behet

Accepted

IgA (elevated in 50% of

patients), IgA (in mesangial
deposits on kidney biopsy)

Berger's disease
Bickerstaff's encephalitis

Anti-GQ1b 2/3 patients

similar to Guillain-Barr
syndrome
overlaps
both sarcoidosis and granu
loma annulare

Blau syndrome
IgG autoantibodies targeting
the type
XVII collagencomponent
of hemidesmosomes

Bullous pemphigoid

[14]

Cancer
Castleman's disease
Celiac disease
Chagas disease

Over expression of IL-6

Accepted[15]
[16][17]

IV??

Anti-tissue transglutaminase
antibodies anti-endomysial IgA, HLA-DQ8 and DQ2.5
anti-gliadin IgA

Suspected[18]

Chronic inflammatory
demyelinating
polyneuropathy

Anti-ganglioside
antibodies:anti-GM1, antiGD1a,anti-GQ1b

Chronic recurrent
multifocal osteomyelitis
Chronic obstructive
pulmonary disease

similar to Guillain-Barr
syndrome
LPIN2, D18S60,similar
to Majeed syndrome

Suspected[19]
[20]

Churg-Strauss syndrome

p-ANCA Eosinophilia[21]

Cicatricial pemphigoid

anti-BP-1, anti BP-2

precipitates C3

Cogan syndrome
Cold agglutinin disease

Accepted

II

IgM

idiopathic or secondary to
leukemia or infection

Complement component 2
deficiency
Contact dermatitis

IV
aka Temporal arteritis;
involves giant cells

Cranial arteritis
Anti-centromere
antibodies Anti-nuclear
antibodies

CREST syndrome

Crohn's disease

Immune
related[22]

Innate
immunity; Th17; Th1; ATG
16L1;CARD15;XBP1;

IV

Cushing's Syndrome

cortisol binding globulin?

Cutaneous leukocytoclastic
angiitis

neutrophils

Dego's disease

Vasculopathy

Dercum's disease

Suspected

Lipoid tissue.[23]
IgA Eosinophilia;[21] antiepidermal transglutaminase
antibodies

Dermatitis herpetiformis

Dermatomyositis

Accepted[24]

Diabetes mellitus type 1

Accepted[7]

histidine-tRNA anti-signal
recognition peptide Anti-Mi2 Anti-Jo1.[25]
IV

B- and T-cell perivascular

inflammatory infiltrate on
muscle biopsy

Glutamic acid decarboxylase HLA-DR3, HLA-DR4

antibodies (GADA), islet cell

Name:

Accepted/
suspected

Hypersensitivit
y
I, II, III, IV

Autoantibody

Notes

antibodies (ICA),
and insulinoma-associated
autoantibodies (IA-2), antiinsulin antibodies
anti-nuclear antibodies, anticentromere and anti-scl70/anti- COL1A2 and TGF-1
topoisomerase antibodies[26]

Diffuse cutaneous
systemic sclerosis
Dressler's syndrome

myocardial neo-antigens
formed as a result of the MI

Drug-induced lupus

Anti-histone antibodies

Discoid lupus
erythematosus

III

IL-2 and IFN-gamma>[27]

LEKTI, SPINK5,[28] filaggrin.,
[29]
Brain-derived
neurotrophic factor (BDNF)
and Substance P.[30]

Eczema
Endometriosis

Suspected[31]

Enthesitis-related
arthritis[32]
Eosinophilic fasciitis

MMP3[33] TRLR2, TLR4,[34] E

RAP1[35]

IgE

IL-3, IL-5, GM-CSF, eotaxin

Accepted

Eosinophilic gastroenteritis
Eosinophilic pneumonia
Epidermolysis bullosa
acquisita

COL7A1

Erythema nodosum
Erythroblastosis fetalis

II

ABO, Rh, Kell antibodies

mother's immune system

attacks fetus

Essential mixed
cryoglobulinemia
Evan's syndrome
Fibrodysplasia ossificans
progressiva

ACVR1 Lymphocytes
express increased BMP4

Fibrosing
alveolitis (orIdiopathic
pulmonary fibrosis)

SFTPA1, SFTPA2, TERT,

and TERC.[36]
serum antiparietal and anti-IF
antibodies

Gastritis
Gastrointestinal
pemphigoid

Accepted

Glomerulonephritis

Sometimes

Goodpasture's syndrome

Accepted[7]

II

Anti-Basement Membrane
Collagen Type IV Protein

Graves' disease

Accepted[7]

II

thyroid autoantibodies (TSHRAb) that activate theTSHreceptor (TSHR)

Guillain-Barr
syndrome(GBS)

Accepted[7]

IV

Anti-ganglioside

Hashimoto's
encephalopathy

Accepted[7]

IV

alpha-enolase[37]

Hashimoto's thyroiditis

Accepted[7]

IV

Henoch-Schonlein purpura

IgA

see Buerger's
disease for IgA; Membrano
us
glomerulonephritis for IgG;
Membranoproliferative/me
sangiocapillary GN
(Complement activation);
Goodpasture's
syndrome; Wegener's
granulomatosis

antibodies against thyroid

HLADR5, CTLA-4
peroxidase and/orthyroglobulin
immunoglobulin A (IgA)
and complement component
3(C3)

Name:

Accepted/
suspected

Hypersensitivit
y
I, II, III, IV

Herpes
gestationis akaGestational
Pemphigoid
Hidradenitis suppurativa

Autoantibody

Notes

IgG and C3 misdirected

antibodies intended to protect
the placenta
Suspected[38]

Hughes-Stovin syndrome
Hypogammaglobulinemia

IGHM, IGLL1, CD79A, BLNK

, LRRC8A, CD79B

Idiopathic inflammatory
demyelinating diseases

a variant of multiple
sclerosis

Idiopathic pulmonary
fibrosis

SFTPA1, SFTPA2, TERT,

and TERC.[36]

Idiopathic
thrombocytopenic
purpura (See Autoimmune
thrombocytopenic
purpura)

Accepted[7]

IgA nephropathy

glycoproteins IIb-IIIa or IbIX, immunoglobulin G

II

III?

IgA produced from marrow

rather than MALT
similar to polymyositis but
does not respond to
steroid therapy-activated
T8 cells

Inclusion body myositis

Chronic inflammatory
demyelinating
polyneuropathy
Interstitial cystitis

anti-ganglioside antibodies
Suspected[39]

Mast cells

Juvenile idiopathic
arthritisaka Juvenile
rheumatoid arthritis
Kawasaki's disease

similar to GuillainBarr
syndrome

inconsistent ANA Rheumatoid

factor
Suspected

ITPKC HLA-B51
voltage-gated calcium
channels; Q-type calcium
channel, synaptogagmin, musc HLA-DR3-B8
arinic acetylcholine receptor
M1

Lambert-Eaton myasthenic
syndrome
Leukocytoclastic vasculitis
Lichen planus
Lichen sclerosus
Linear IgA disease (LAD)
Lupoid
hepatitis akaAutoimmune
hepatitis

ANA and SMA,[40] LKM-1, LKM2 or LKM-3; antibodies

against soluble liver antigen[41]
[42]
(anti-SLA, anti-LP) no
autoantibodies detected
(~20%)[citation needed]

Lupus erythematosus

Anti-nuclear antibodies [43] antiRo.[44] Also, they are often

present in Sjgren's syndrome.
[45][46]
Eosinophilia[21]

Accepted[7]

III

Majeed syndrome

LPIN2

Mnire's disease

III?

Microscopic polyangiitis
Miller-Fisher
syndrome seeGuillainBarre Syndrome
Mixed connective tissue
disease
Morphea
Mucha-Habermann
diseaseaka Pityriasis

major peripheral myelin

protein P0[47]
p-ANCA myeloperoxidase

Accepted
Accepted[7]

binds to neutrophils
causing them to
degranulate and damages
endothelium

anti-GQ1b
anti-nuclear antibody anti-U1HLA-DR4
RNP

Suspected[48]
T-cells

Name:

Accepted/
suspected

Hypersensitivit
y
I, II, III, IV

Autoantibody

Notes

lichenoides et varioliformis
acuta

Multiple sclerosis

Accepted[49]

IV

Anti-Kir4.1 (heterogeneous)[49]

Autoantibody against
potassium channel. Also
invoved HLA-DR2, PECAM1[50] Anti-myelin basic
protein

Myasthenia gravis

Accepted[7]

II

nicotinic acetylcholine
receptor MuSK protein

HA-B8 HLA-DR3 HLA-DR1

Microscopic colitis

Suspected
see Dermatomyositis and
Polymyositis seeInclusionbody-myositis

Myositis
Narcolepsy[51][52]

Accepted

Neuromyelitis optica (also

Devic's disease)
Neuromyotonia

Suspected[57]

Occular cicatricial
pemphigoid
Opsoclonus myoclonus
syndrome

Suspected

II?

hypocretin or orexin[53]

II?

NMO-IgG aquaporin 4.[55][56]

II?

voltage-gated potassium
channels.[57]

II?

BP-1, BP-2

HLA-DQB1*0602[54]

C3 deposition
Lymphocyte recruitment
to CSF[58]

IV?

Ord's thyroiditis
anti-cyclic citrullinated
peptide antibodies (anti-CCP)
and antikeratin antibodies
(AKA)[59]

Palindromic rheumatism
PANDAS (pediatric
autoimmune
neuropsychiatric disorders
associated with
streptococcus)

Suspected

Paraneoplastic cerebellar
degeneration
Paroxysmal nocturnal
hemoglobinuria (PNH)

antibodies against
streptococcal infection
serve as auto-antibodies

II?

IV?[60] II?

anti-Yo[61] (anti-cdr-2[62] in
purkinje fibers) anti-Hu, anti-Tr,
antiglutamate receptor

Sometimes(?
)

complement attacks RBCs

Parry Romberg syndrome

ANA

Parsonage-Turner
syndrome
Pars planitis
Pemphigus vulgaris

Accepted[7]

II

Anti-Desmoglein
3 eosinophilia[21]

Pernicious anaemia

Accepted[63]

II

anti-parietal cell antibody

Perivenous
encephalomyelitis
interleukin 1, interleukin
6 and TNF. vascular
endothelial growth
factor (VEGF), given the .

POEMS syndrome

[64]

Polyarteritis nodosa
Polymyalgia rheumatica
Polymyositis

Primary biliary cirrhosis

Accepted[24]

Accepted[65]

IFN-gamma, IL-1, TNF-alpha

Anti-p62, Anti-sp100, AntiMitochondrial(M2)Anti-Roaka
SSA.[44] Also, they are often
present in Sjgren's syndrome.
[45][46]

Primary sclerosing
cholangitis
Progressive inflammatory
neuropathy

HLA-DR52a
Suspected

overlap with primary

biliary cirrhosis?

Accepted/
suspected

Hypersensitivit
y
I, II, III, IV

Psoriasis

Accepted[66]

IV?

CD-8 T-cells, HLA-Cw6, IL12b, IL-23b, TNFalpha, NFB

Psoriatic arthritis

Accepted[67]

IV?

HLA-B27

Name:

Autoantibody

Notes

Can occur in conjunction

with other immune-related
disorders

Pyoderma gangrenosum
Pure red cell aplasia
Rasmussen's encephalitis

anti-NR2A antibodies

Raynaud phenomenon

Suspected

Relapsing polychondritis

Accepted[68]

Can occur in conjunction

with other immune-related
disorders

Reiter's syndrome

Restless leg syndrome

May occur in Sjgren's

syndrome, celiac disease,
and rheumatoid arthritis
or in derangements of iron
metabolism

Suspected

Retroperitoneal fibrosis
III

Rheumatoid factor (antiIgGFc), AntiMCV,ACPAs(Vimentin

Accepted[69]

II

streptococcal M protein cross

reacts with humanmyosin,[70]

Suspected

IV[71][72]

Rheumatoid arthritis

Accepted

Rheumatic fever
Sarcoidosis
Schizophrenia

[7]

HLA-DR4, PTPN22,
depleted B cells, TNF
alpha,IL-17, (also maybe
IL-1, 6, and 15)

BTNL2; HLA-B7-DR15; HLA

DR3-DQ2.[73]

Suspected[74]
[75][76]

Schmidt syndrome another

form of APS

anti-21 hydroxylase, anti-17

hydroxylase[77]

Schnitzler syndrome

DQ2, DQ8 and DRB1*0404

IgM?

Scleritis
Scleroderma

Suspected[48]

Serum Sickness
Sjgren's syndrome

IV?

Scl-70 Anti-topoisomerase

dysregulated apoptosis?

III
anti-Ro.[44] Also, they are often
present in Sjgren's syndrome.

Accepted[7]

[45][46]

Spondyloarthropathy

HLA-B27

Still's disease see Juvenile

Rheumatoid Arthritis
Stiff person syndrome

ANA
glutamic acid
decarboxylase (GAD),[79]

Suspected

Subacute bacterial
endocarditis (SBE)

III

[80]

macrophage migration
inhibitory factor[78]
GLRA1 (glycine receptor)

essential mixed
cryoglobulinemia

Susac's syndrome
Sweet's syndrome

GCSF

Sydenham
chorea seePANDAS
ocular antigens following
trauma

Sympathetic ophthalmia
Systemic lupus
erythematosus see Lupus
erythematosus

III

Takayasu's arteritis
Temporal arteritis (also
known as "giant cell
arteritis")
Thrombocytopenia

Accepted[7]

IV
II

glycoproteins IIb-IIIa or Ib-IX in multiple mechanisms

ITP anti-ADAMTS13 inTTP.

Name:

Accepted/
suspected

Hypersensitivit
y
I, II, III, IV

Autoantibody

Notes

and HUS anti-cardiolipin

(anti-cardiolipin antibodies)
and 2 glycoprotein
I in Antiphospholipid
syndrome anti-HPA-1a, antiHPA-5b, and others[82] inNAIT
[81]

Tolosa-Hunt syndrome

Transverse myelitis

Transverse Myelitis is a
rare neurological disorder
that is part of a spectrum
of neuroimmunologic
diseases of the central
nervous
system. http://www.myeliti
s.org/

Accepted

Ulcerative colitis (one of

two types of idiopathic
inflammatory bowel
disease "IBD")

Accepted[7]

Undifferentiated
connective tissue
disease different from
Mixed connective tissue
disease

Accepted

IV

anti-nuclear antibody

HLA-DR4

II?

anti C1q antibodies[83]

clinically may resemble

type I hypersensitivity!

III

sometimes ANCA

Undifferentiated
spondyloarthropathy
Urticarial vasculitis
Vasculitis
Vitiligo

Wegener's granulomatosis

Accepted[14]

NALP-1 RERE, PTPN22,

LPP, IL2RA, GZMB,
UBASH3A and C1QTNF6

Suspected[84]
[85]

Accepted[86]

Anti-neutrophil
cytoplasmic(cANCA)

Development of therapies
In both autoimmune and inflammatory diseases, the condition arises through aberrant reactions of the human
adaptive or innate immune systems. In autoimmunity, the patients immune system is activated against the body's
own proteins. In chronic inflammatory diseases, neutrophils and other leukocytes are constitutively recruited by
cytokines and chemokines, leading to tissue damage.
Mitigation of inflammation by activation of anti-inflammatory genes and the suppression of inflammatory genes in
immune cells is a promising therapeutic approach