HYPERSENSITIVITY DISEASES

is reactivity of an host to an agent on a second or'

.'subsequent occasion
Hypersensitivity reactions include
autoimmune and -2-allergic conditions-1
AUTOIMMUNE DISEASE-1
Autoimmunity can be defined as the presence of immune
responses against self-tissue
CHARACTERISED BY present of auto antibody and auto
reactive T cells
.
Type of autoimmune disease
A-Organ-specific
Immune response directed against localised antigens
Graves' disease
Hashimoto's thyroiditis
Addison's disease
Pernicious anaemia
Type 1 diabetes
Idiopathic thrombocytopenic purpura
Autoimmune haemolytic anaemia
Myasthenia gravis
Rheumatoid arthritis
Dermatomyositis
.
B-Multisystem⚫
Immune response directed to⚫
widespread target antigens. E.g
,Systemic sclerosis ⚫
Mixed connective tissue disease ⚫
SLE ⚫
.of autoimmunity(PATHOPHYSIOLOGY) ⚫
Immunological tolerance-1 ⚫
Failure of immune system distinguishes self from foreign ⚫
,tissue
Here, T and B lymphocytes that recognize self antigens are . ⚫
eliminated before they develop into fully immune competent
..cells
Factors predisposing to autoimmune disease-2 ⚫
.Both A- genetic and B-environmental factors contribute-1 ⚫
The most important genetic determinants of autoimmune . ⚫
,susceptibility are the HLA genes
HLA associations in autoimmune disease ⚫
.

Several environmental factors can trigger autoimmunity in

.genetically predisposed individuals
infection, as occurs in acute rheumatic fever following-1
streptococcal infection or reactive arthritis following bacterial
infection. A number of mechanisms have been responsible ,
such as a-cross-reactivity between the infectious pathogen and
,self determinants (molecular mimicry)
Failure of self-tolerance results in immune responses against
self-antigens.9 Such reactions are called autoimmunity and may
give rise to chronic inflammatory autoimmune disease
a side-effect of drug treatment. For example,-2 ⚫
the metabolic products of the anaesthetic agent
halothane bind to liver enzymes, resulting in a
structurally novel protein. This is recognised as
a new (foreign) antigen by the immune system,
and the autoantibodies and activated T cells
.directed against it may cause hepatic necrosis
Classification of autoimmune
diseases
⚫ 1-classified as organ-specific or multisystem
⚫ 2-mechanism responsible for tissue damage. The Gell and
Coombs classification of hypersensitivity
⚫ Type Mechanism Example of disease in response to exogenous agent Example of autoimmune disease

⚫ Type I
⚫ Immediate hypersensitivity
⚫ IgE-mediated mast cell degranulation
⚫ e.g Allergic disease
Type II
Antibody-mediated ⚫
Binding of cytotoxic IgG or IgM antibodies to antigens on cell ⚫
surface causes cell killing
ABO blood transfusion reaction-1 ⚫
Hyperacute transplant rejection-2
hemolytic anemia ⚫
Idiopathic thrombocytopenic purpura ⚫
Good pasture's disease ⚫
Type II hypersensitivity reactions are caused by chemical ⚫
modification of cell surface or matrix-associated antigens
that generates “foreign” epitopes to which the immune
system is not tolerant. B cells respond to this antigenic
challenge by producing IgG, which binds to these
modified cells and renders them susceptible to destruction
through complement activation, phagocytosis, and
antibody-dependent cytotoxicity
Tissue-bound autoantibodies activate monocytes, ⚫
neutrophils, and basophils through FcγRs, initiating
release of proteases, reactive oxidants, cytokines, and
prostaglandins. Local activation of complement,
particularly C5a, recruits and activates inflammatory cells
and amplifies tissuNeighboring cells are lysed by
assembly of the membrane attack complex or by
FcγR-initiated, antibody-dependent cytotoxicity.e injury
Type III
⚫ Immune complex-mediated
⚫ IgG or IgM antibodies bind soluble antigen to form
immune complexes which trigger classical
complement pathway activation
⚫ E.g 1-Serum sickness
⚫ 2-Farmer's lung
⚫ e.gSLE
Type IV

Delayed type
Activated T cells, phagocytes and NK cells
e.g 1-Acute cellular transplant rejection
1-Type 1 diabetes Nickel hypersensitivity-2

Hashimoto's thyroiditis-3
rheum. arth -4
Type IV responses are mediated by T cells through three ⚫
.different pathways
In the first, type 1 helper T (TH1) cells recognize soluble ⚫
antigens (Ag) and release interferon-γ (IFN-γ) to activate
effector cells, in this case macrophages (MΦ), and cause tissue
.injury
In TH2-mediated responses, eosinophils predominate. TH2 ⚫
cells produce cytokines to recruit and activate eosinophils,
leading to their degranulation and tissue injury lymphocytes
.(CTLs)
In the third pathway, damage is caused directly by cytolytic T ⚫
.cells
Type I hypersensitivity is relevant in allergy but is not associated with
autoimmune disease.

In type II hypersensitivity, injury is localised to a single tissue or organ.

Type III hypersensitivity is a generalised reaction resulting from immune

complex deposition in blood vessel walls, skin, joints and glomeruli, where
they cause a chronic inflammatory response. gives rise to systemic diseases
such as SLE.

In type IV hypersensitivity, activated T cells and macrophages mediate

phagocytosis and NK cell recruitment.
It is referred to as a delayed response in that it will usually ⚫
require –24-72 hours at a minimum for signs of
inflammation to occur locally
Delayed hypersensitivity is a major mechanism of defense ⚫
against various intracellular pathogens, including
mycobacteria, fungi, and certain parasites, and it occurs in
transplant rejection and tumor immunity
These diseases are caused by pathogens which represent a ⚫
persistent, chronic, antigenic stimulus
The reactions are elicited by interaction of cells ⚫
and mediators which comprise: (1) induration
(the granulomatous type); (2) swelling and induration, and
possibly fever (the tuberculin type); and (3) eczema (the
contact type)
 Investigations in autoimmunity

Autoantibodies ;can be identified in the-

laboratory, and are useful in disease diagnosis
.and monitoring
Rheumatoid factor-
A rheumatoid factor is an antibody directed
against the common (Fc) region of human IgG.
Rheumatoid factors may be of any
immunoglobulin class but IgM is most commonly
tested
CONDITIONS ASSOCIATED WITH A
POSITIVE RHEUMATOID FACTOR
(%) Disease Frequency ⚫
% Rheumatoid arthritis with extra-articular manifestations 100 ⚫
Rheumatoid arthritis (overall) 75% ⚫
% Sjögren's syndrome 90 ⚫
% Primary biliary cirrhosis 50 ⚫
% Subacute bacterial endocarditis 40 ⚫
% SLE 30 ⚫
Tuberculosis 15% ⚫
Elderly (> 65 years) 20 ⚫
Only 50% of patients with rheumatoid arthritis are positive for
rheumatoid factor at the time of diagnosis; a further 25% will
become seropositive in the first 2 years of disease (. Thus this test
is insufficiently sensitive to rule out rheumatoid arthritis. In
addition, rheumatoid factor has low specificity for rheumatoid
arthritis, being associated with a wide variety of autoimmune and
non-autoimmune conditions, and a common finding in the elderly
(). The major indication for rheumatoid factor testing is to
evaluate prognosis in rheumatoid arthritis, as it is associated with
more severe erosive disease and extra-articular disease
. .manifestations such as nodules, vasculitis and Felty's syndrome
Anti-CCP antibody

Antibodies to cyclic citrullinated peptide (anti-CCP ⚫

antibodies) bind to peptides in which the amino acid
arginine has been converted to citrulline by
peptidylarginine deiminase, an enzyme abundant in the
inflamed synovium. It is a more specific test for
rheumatoid arthritis than rheumatoid factor and a better
predictor of an aggressive disease course. In patients
with undifferentiated arthritis, anti-CCP antibodies
may predict those who are likely to develop
.rheumatoid arthritis
Antinuclear antibodies
CONDITIONS ASSOCIATED WITH A POSITIVE ⚫
ANTINUCLEAR ANTIBODY
SLE ∼100% ⚫
Scleroderma 60-80% ⚫
Sjögren's syndrome 40-70% ⚫
Dermatomyositis or polymyositis 30-80% ⚫
Mixed connective tissue disease 100% ⚫
.N.B. 5% of healthy individuals have an ANA titre > 1:80 ⚫
Antinuclear antibodies (ANA) are a group of
antibodies which bind to components of the nucleus.
The major indication for ANA testing is in the
diagnosis of SLE, where it has a very high sensitivity
(almost 100%), and a negative ANA test virtually
excludes the diagnosis. However, the specificity is
low (, and ANA may be present in low titre in healthy
individuals.
Anti-DNA antibodies bind to double-stranded DNA and are
highly specific for SLE (95%). They occur in up to 60% of SLE
.patients at some time in their disease course
Antiphospholipid antibodies
Antiphospholipid antibodies are associated with the development
of venous and arterial thrombosis and recurrent fetal loss. This
may occur in isolation (primary antiphospholipid syndrome), or
as a complication of SLE (secondary antiphospholipid
.syndrome)
but the most commonly measured are ,
.anticardiolipin antibodies and lupus anticoagulant
.
Measures of complement activation-2 ⚫
Measuring complement useful in the evaluation of immune ⚫
complex-mediated diseases(type III). Classical complement
pathway activation leads to a decrease in circulating C4, and
decreased C3 levels. Serial measurement of C3 and C4 is a
.useful surrogate measure of immune complex formation

C-reactive protein (CRP)-3 ⚫

Erythrocyte sedimentation rate (ESR)-4 ⚫
Secondary immune deficiencies-2
Physiological ⚫
Ageing , Pregnancy Prematurity • ⚫
Infection • • ⚫
HIV ,Measles ,Mycobacterial infection • ⚫
Iatrogenic ⚫
Immunosuppressive therapy Antineoplastic agents • ⚫
Corticosteroids ,Stem cell transplantation ,Radiation injury • ⚫
Anti-epileptic agents •
Malignancy ⚫
B-cell malignancies including leukaemia, lymphoma and • ⚫
myeloma Solid tumours Thymoma
⚫
Biochemical and nutritional disorders ⚫
Malnutrition • ⚫
Renal insufficiency/dialysis • ⚫
Diabetes mellitus • ⚫
Specific mineral deficiencies, e.g. iron, zinc • ⚫
Other conditions ⚫
Burns • ⚫
Asplenia/hyposplenism • ⚫