Transcript Autoimmune Disorders

Dr Shoaib Raza
Autoimmune Disorders

 Immune reactions against self antigens
 Affects 1% to 2% of US population
 Requirements for an autoimmune disorder:
 Presence of immune reaction specific for some selfantigen or self-tissue
 Evidence that the reaction is not secondary to tissue
damage
 Absence of another well defined cause of disease
 DIAGNOSIS OF EXCLUSION
Autoimmune Disorders

 Clinical manifestations are varied
 Organ specific disease
 Type 1 diabetes mellitus
 Multiple sclerosis
 Systemic or generalized diseases
 Systemic lupus erythematosus
 Middle of the spectrum
 Goodpasture’s syndrome
Immunologic Tolerance

 The phenomenon of unresponsiveness to an antigen
as a result of exposure to lymphocytes to that
antigen.
 Self tolerance refers to lack of responsiveness to an
individual’s own antigen
 Central tolerance
 Peripheral tolerance
Central Tolerance

 Immature self reactive T or B-Cell clones that
recognize self-antigens during their maturation in
the central lymphoid organs (Thymus or Bone
marrow) are killed or rendered harmless.
 Central tolerance is however far from PERFECT
 Self reactive T or B-cells may skip the central
tolerance and enter the circulation
Central Tolerance of T-Cells

 In the thymus
 Negative selection:
 Self reactive T-Cells die by apoptosis
 AIRE protein stimulates expression of “peripheral tissue
restricted” self-antigens in the thymus
 Some self reactive CD4+ T-Cells in the thymus do not
die, but later on develop into regulatory cells
Central Tolerance of B-Cells

 In the bone marrow:
 Receptor editing:
 Some self-reactive B-Cells reactivate the machinery of
antigen receptor gene and begin to express new antigens
receptors
 If receptor editing does not occur, self-reactive B-Cells
undergo apoptosis
Peripheral Tolerance

 Several mechanisms
 Anergy
 Prolonged or irreversible inactivation of lymphocytes
 Absence of co-stimulatory signals induce apoptosis
 Suppression by regulatory T-Cells
 Mainly developed in thymus
 May be developed in peripheral tissues
 ? immunosuppressive cytokines are released (IL-10)
 Deletion by activation-induced cell death
 Self-reactive CD4+ T-Cells undergo apoptosis
Mechanism of Autoimmunity

 Autoimmunity arises from a combination of
 Inheritance of susceptibility genes may lead to breach
in self-tolerance
 Environmental triggers e.g. infections and tissue
damage
Role of Infection in Autoimmune Diseases

 Many autoimmune diseases are:
 Associated with infections
 Up-regulation of expression of co-stimulators on APC
 Molecular mimicry (e.g. rheumatic heart disease)
 Polyclonal B-Cell activation (e.g. EBV infection)
General Features of Autoimmune Diseases

 Autoimmune diseases are PROGRESSIVE, with
relapses and remissions
 Clinical and pathological manifestations are
determined by nature of underlying immune
response
 Different autoimmune diseases show substantial
clinical, serological and pathological overlap.
Systemic Lupus Erythematosus
(SLE)

 Prototype of multisystem disease of autoimmune origin
 Antinuclear antibodies (ANAs) are usually present
 Acute or insidious in onset
 Chronic, remitting and relapsing, often febrile illness
characterized principally by injury to the skin, joints, kidney
and serosal membranes
 Complex set of criteria for establishing the diagnosis
Etiology & Pathogenesis

 Exact cause is unknown
 Failure of the mechanisms that maintain selftolerance
 Genetic factors
 Immunologic factors
 Environmental factors
Mechanism of Tissue Injury

 Most of the visceral lesions are caused by Type III
Hypersensitivity reaction
 DNA-AntiDNA complexes are formed
 Immune complex nature of the disease
 Autoantibodies specific for RBC, WBC and platelets,
opsonize these cells for phagocytosis
 SLE is a complex disorder of multifactorial origin
resulting from genetic, immunologic and environmental
factors that act in concert to cause activation of helper TCells and B-Cells and result in the production of several
species of pathologic autoantibodies.
Morphology

 Kidney:
 Lupus nephritis
 Joints:
 Synovitis, arthritis etc
 CNS:
 Due to acute vasculitis
 Heart:
 Pericarditis, non-bacterial verrucous endocarditis
 Lungs, Spleen, etc.
 Splenomegaly, pleuritis
Clinical Features

 Variable presentation according to organ involved
 Unpredictable presentation and course of the disease
 Chronic discoid lupus erythematosus
 Subacute cutaneous lupus erythematosus
Rheumatoid Arthritis

 Chronic systemic inflammatory disease that
principally affects joints
 Non-suppurative proliferative and inflammatory
synovitis
 Often progress to ankylosis
 Genetic susceptibility
 Arthritogenic antigen
 Autoimmunity
 Anti IgG antibody (Fc portion)
Sjögren Syndrome

 Chronic disease, characterized by:
 Keratoconjunctivitis sicca (Dry Eyes)
 Xerostomia (Dry mouth)
 Immunlogically mediated destruction of the lacrimal
and salivary glands
 May be associated with other autoimmune disorders
 SLE, RA, polymyositis, scelroderma, vasculitis,
thyroiditis, MCTD, etc.
Systemic sclerosis (Scleroderma)

 Chronic disease characterized by:
 Chronic inflammation as a result of autoimmunity
 Widespread damage to small blood vessels
 Progressive interstitial and perivascular fibrosis
 CREST syndrome
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Calcinosis
Raynaud’s disease
Esophageal dysmotility
Sclerodactyly
Telangiectasia
Mixed Connective Tissue Diseases

 Clinical features, mixture of
 SLE
 Systemic sclerosis
 Polymyositis
 Serologically characterized by:
 Autoantibodies to ribonucleotide particle containing
U1 ribonucleoprotein.
Polyarteritis Nodosa

 Necrotizing inflammation of small sized blood vessel
wall
 Small size blood vessels of lungs and kidneys are
usually affected