Dr Shoaib RazaDr Shoaib Raza

Immune reactions against self antigens Affects 1% to 2% of US population Requirements for an autoimmune disorder:

Presence of immune reaction specific for some self-antigen 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

Autoimmune Disorders

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

Immunologic 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

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 T-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

Central Tolerance of B-Cells

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

Peripheral Tolerance

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

Mechanism of Autoimmunity

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)

Role of Infection in 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.

General Features of Autoimmune Diseases

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

Systemic Lupus Erythematosus (SLE)

Exact cause is unknown Failure of the mechanisms that maintain self-

tolerance Genetic factors Immunologic factors Environmental factors

Etiology & Pathogenesis

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 T-Cells and B-Cells and result in the production of several species of pathologic autoantibodies.

Mechanism of Tissue Injury

Kidney:

Lupus nephritis Joints:

Synovitis, arthritis etc CNS:

Due to acute vasculitis Heart:

Pericarditis, non-bacterial verrucous endocarditis Lungs, Spleen, etc.

Splenomegaly, pleuritis

Morphology

Variable presentation according to organ

involved Unpredictable presentation and course of the

disease Chronic discoid lupus erythematosus Subacute cutaneous lupus erythematosus

Clinical Features

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)

Rheumatoid Arthritis

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.

Sjögren Syndrome

Chronic disease characterized by:

Chronic inflammation as a result of autoimmunity Widespread damage to small blood vessels Progressive interstitial and perivascular fibrosis

CREST syndrome Calcinosis Raynaud’s disease Esophageal dysmotility Sclerodactyly Telangiectasia

Systemic sclerosis (Scleroderma)

Clinical features, mixture of

SLE Systemic sclerosis Polymyositis

Serologically characterized by: Autoantibodies to ribonucleotide particle

containing U1 ribonucleoprotein.

Mixed Connective Tissue Diseases

Necrotizing inflammation of small sized blood

vessel wall Small size blood vessels of lungs and kidneys

are usually affected

Polyarteritis Nodosa