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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 self-antigen or self-tissue

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autoimmune disorders

Autoimmune Disorders

Dr Shoaib Raza

autoimmune disorders1
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 self-antigen or self-tissue
    • Evidence that the reaction is not secondary to tissue damage
    • Absence of another well defined cause of disease
autoimmune disorders2
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
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
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
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
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
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
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
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
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
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
Etiology & Pathogenesis
  • Exact cause is unknown
  • Failure of the mechanisms that maintain self-tolerance
    • Genetic factors
    • Immunologic factors
    • Environmental factors
mechanism of tissue injury
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 T-Cells and B-Cells and result in the production of several species of pathologic autoantibodies.
  • 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
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
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)
sj gren syndrome
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
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
    • Calcinosis
    • Raynaud’s disease
    • Esophageal dysmotility
    • Sclerodactyly
    • Telangiectasia
mixed connective tissue diseases
Mixed Connective Tissue Diseases
  • Clinical features, mixture of
    • SLE
    • Systemic sclerosis
    • Polymyositis
  • Serologically characterized by:
    • Autoantibodies to ribonucleotide particle containing U1 ribonucleoprotein.
polyarteritis nodosa
Polyarteritis Nodosa
  • Necrotizing inflammation of small sized blood vessel wall
  • Small size blood vessels of lungs and kidneys are usually affected