By: Dr Puneet Kumar Gupta Assistant Professor, Microbiology Autoimmunity For MBBS (28/11/2017) By: Dr Puneet Kumar Gupta Assistant Professor, Microbiology

Tolerance and Autoimmunity

What is tolerance? Mechanisms to protect from potentially self reacting lymphocytes. Central tolerance: In primary lymphoid organs (BM & Thymus) Peripheral tolerance: Secondary Lymphoid tissue

Mechanism of Central tolerance Negative selection (by apoptosis) Receptor Editing (Antigen receptor gene rearrangement)

Mechanism of peripheral tolerance Ignorance: Never encounter Self Ag Anergy: unresponsiveness Self reactive T cell interact with APC but co-stimulatory signal blocked Immunomodulatory molecules like CTLA4 binding instead of CD 28 on T cell Phenotypic skewing: after activation via APC (with Self Ag)---Non pathogenic cytokines release Activated self reactive Tcell---Upregulation of Fas Ligand---apoptosis Regulatory T cells (TREG Cells)-can down regulate self reactive T cell (by IL-10, TGF-b) Sequestration of self Ag: lens protein

Antigen can be Tolerogen or Immunogens Co-stimulatory molecules play an important role Tolerance is antigen specific

Failure of tolerance Autoimmunity Failure of Tolerance to protect host from self-reacting lymphocytes Destruction of self proteins, cells, and organs by auto-antibodies or self-reactive T cells 3% to 8% of individuals in the industrialized world

Factors responsible for promoting tolerance High dose of antigen Persistence of antigen Route of administration Adjuvents Low level of co-stimulators Presentation of antigen by immature/unactivated antigen-presenting cells (APCs)

All together Autoimmunity may be due to immunological, Genetic, Viral, Drug induced, & hormonal mechanisms Number of immunological mechanism  all leading to abnormal B or T-cell production. Most instances Diseases by multiple mechanism  difficulty in Rx

Mechanisms Antigenic alteration Sequestered Ag Cross reacting foreign Ag Molecular mimicry Polyclonal activation of B cell Forbidden clones Altered T or B cell function

Antigenic alteration Neoantigen formation Physical- Irradiation, photosensitivity, cold allergy Chemical- Drug induced anemia, Lecopenia, thrombocytopenia Biological injury-Viral infection (infectious mononucleosis etc) intracellular pathogen

Sequestered Ag Sequestered Ag: Self Ab present in closed system not accessible to immune system Lens protein Immunological tolerance not established during foetal life Penetrating injury---leak of lens protein—immune response—injury to other eye

Sequestered Ag Sperm Ag—Puberty Mumps---damage to BM seminiferous tubules—immune response---Orchitis

Cross reacting foreign Ag Similary b/w some foreign & Self Ag Indivisual Nerve tissue damage-antirabies immunization of human with neural vaccine of infected sheep brain Streptococcal M protein—heart ms—Heart damage Nephritogenic strain streptococcus-- GN

Molecular mimicry Identical peptide sequence in epitopes b/w microorganism & Self Ag HLA B27- Arthritogenic strain of S. flexneri Joint membrane- M. tuberculoisis Myocardium- Coxsackie B virus

Polyclonal activation of B cell Ag--- corresponding B cell activation Polyclonal activation of B cells: Chemical (2 ME) Bacterial product (PPD, LPS) Enz (Trypsin) Antibotics (Nystatin) Infection (Mycoplasma, EBV, Malaria)

Forbidden clones Breakdown of immunological homeostasis lead to cessation of tolerance & emergence of forbidden clones of immunocompetent cell----immune response against self Ag Injection of Self Ag with Freunds’s adjuvant

Altered T or B cell function Enhanced Helper T cell ↓↓ Suppressor T cell function Defect in thymus Stem cell development Macrophage function Idiotype-antiidiotype network defect

Hemocytolytic autoimmune Ds Autoimmune Hemolytic anaemia Cold autoAb—IgM Ab—agglutinate RBC at 40C Following syphilis, 10atyptical pneumonia, Malaria, Trypanosomiasis Warm AutoAb-IgG Ab-Non agglutinating Drugs-sulphonamide, antibiotics, alpha methyldopa RBC coated with Ab—destroyed in spleen

Hemocytolytic autoimmune Ds Autoimmune Thrombocytopenia—ITP Autoimmune Leucopenia- Non agglutinating Antileucocyte Ab serum of patient with SLE, RA

Localised Organ Specific Ds

Disease Hashimoto’s Ds Enlargement of thyroid Hypothyrodism or Frank myxedma Glandular structure-replacement with lymphoid tissue Ab- to thyoglobulin, acinar colloid, Microsomal Ag, thyroid cell surface components Thyrotoxicosis (Grave’s Ds) ↑↑↑ hormone IgG Ab (to thyroid membrane Ag) act as Long acting thyroid stimulator (LATS) Addison ds Lymphocytic infiltration of adrenal & circulating Ab to Zona glomerulosa Autoimmune orchitis Mumps Lymphocytic infiltration of Testes & circulating Ab to sperm & germinal cell

Disease Myasthenia gravis Thyorid lymphoid hyperplasia Numerous germinal center Ab Ach Receptor on myoneural junction of striated Ms---impairment of Ms Contraction Autoimmune Ds of eye Phacoanaphylaxis- Cataract Sx –intraocular inflammation Symathetic ophthamia- Performating injury to one eye Pernicious Anaemia Ab to parietal cell of gastric mucosa- Achlorhydria, Atrophic gastritis Ab to Intrinsic Factor---Vit B12 def Autoimmune Ds of Nervous system Neuroparalytic accidents following- neural vaccine—Rabies GBS- idiopathic polyneuritis Autoimmune ds of Skin Pemphigus vulgaris- Ab to intracellular adhesion protein desmoglein Bullous pemphigoid- Ab dermoepidermal junction Ab in Dermatitis herpetiformis

SLE Biological False +ve STS Variety of AutoAb Nuclei Intracytoplasmic cell constituents Thyroid & other organs LE cell- Neutrophils containing LE Bodies (large pale homogenous body) almost filling cytoplasm Antinuclear Ab (ANA)—Sensitive but not specific Pattern: homogenous, Peripheral, speckled, nucleolar Anti DNA Ab- ds, ss, both Anti-ds DNA Ab & Anti sm Ab---specific for SLE

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