Autoimmunity For MBBS (28/11/2017) - PowerPoint Presentation

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Autoimmunity

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

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Tolerance and Autoimmunity

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What is tolerance?

Mechanisms to protect from potentially self reacting lymphocytes. Central tolerance: In primary lymphoid organs (BM & Thymus)Peripheral tolerance: Secondary Lymphoid tissue10

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

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Mechanism of peripheral toleranceIgnorance: Never encounter Self Ag

Anergy: unresponsivenessSelf reactive T cell interact with APC but co-stimulatory signal blockedImmunomodulatory molecules like CTLA4 binding instead of CD 28 on T cellPhenotypic skewing: after activation via APC (with Self Ag)---Non pathogenic cytokines releaseActivated self reactive Tcell---Upregulation of Fas Ligand---apoptosisRegulatory T cells (TREG Cells)-can down regulate self reactive T cell (by IL-10, TGF-b)Sequestration of self Ag: lens protein14

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Antigen can be Tolerogen or Immunogens

Co-stimulatory molecules play an important roleTolerance is antigen specific16

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Failure of tolerance Autoimmunity

Failure of Tolerance to protect host from self-reacting lymphocytesDestruction of self proteins, cells, and organs by auto-antibodies or self-reactive T cells3% to 8% of individuals in the industrialized world17

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Factors responsible for promoting tolerance

High dose of antigenPersistence of antigenRoute of administrationAdjuventsLow level of co-stimulatorsPresentation of antigen by immature/unactivated antigen-presenting cells (APCs)18

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All togetherAutoimmunity 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 Rx21

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Mechanisms

Antigenic alterationSequestered AgCross reacting foreign AgMolecular mimicryPolyclonal activation of B cellForbidden clonesAltered T or B cell function24

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Antigenic alterationNeoantigen

formationPhysical- Irradiation, photosensitivity, cold allergyChemical- Drug induced anemia, Lecopenia, thrombocytopeniaBiological injury-Viral infection (infectious mononucleosis etc) intracellular pathogen25

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Sequestered AgSequestered

Ag: Self Ab present in closed system not accessible to immune systemLens proteinImmunological tolerance not established during foetal lifePenetrating injury---leak of lens protein—immune response—injury to other eye26

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Sequestered AgSperm Ag—Puberty

Mumps---damage to BM seminiferous tubules—immune response---Orchitis27

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Cross reacting foreign AgSimilary

b/w some foreign & Self AgIndivisual Nerve tissue damage-antirabies immunization of human with neural vaccine of infected sheep brainStreptococcal M protein—heart ms—Heart damageNephritogenic strain streptococcus-- GN28

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Molecular mimicryIdentical peptide sequence in epitopes b/w microorganism & Self Ag

HLA B27- Arthritogenic strain of S. flexneriJoint membrane- M. tuberculoisisMyocardium- Coxsackie B virus29

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Polyclonal activation of B cellAg--- corresponding B cell activation

Polyclonal activation of B cells:Chemical (2 ME)Bacterial product (PPD, LPS)Enz (Trypsin)Antibotics (Nystatin)Infection (Mycoplasma, EBV, Malaria)31

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Forbidden clones

Breakdown of immunological homeostasis lead to cessation of tolerance & emergence of forbidden clones of immunocompetent cell----immune response against self AgInjection of Self Ag with Freunds’s adjuvant 32

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Altered T or B cell functionEnhanced Helper T cell

↓↓ Suppressor T cell functionDefect in thymusStem cell developmentMacrophage functionIdiotype-antiidiotype network defect33

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Hemocytolytic autoimmune Ds

Autoimmune Hemolytic anaemiaCold autoAb—IgM Ab—agglutinate RBC at 40CFollowing syphilis, 10atyptical pneumonia, Malaria, Trypanosomiasis Warm AutoAb-IgG Ab-Non agglutinating Drugs-sulphonamide, antibiotics, alpha methyldopaRBC coated with Ab—destroyed in spleen40

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Hemocytolytic autoimmune Ds

Autoimmune Thrombocytopenia—ITPAutoimmune Leucopenia-Non agglutinating Antileucocyte Ab serum of patient with SLE, RA41

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Localised Organ Specific Ds

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Disease

Hashimoto’s DsEnlargement of thyroidHypothyrodism or Frank myxedmaGlandular structure-replacement with lymphoid tissueAb- to thyoglobulin

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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

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Disease

Myasthenia gravisThyorid lymphoid hyperplasia Numerous germinal centerAb Ach Receptor on myoneural junction of striated Ms---impairment of Ms Contraction

Autoimmune

Ds of eye

Phacoanaphylaxis

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Cataract

Sx

–intraocular inflammation

Symathetic

ophthamia

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Performating

injury

to one eye

Pernicious

Anaemia

Ab to parietal cell of gastric mucosa-

Achlorhydria

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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

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SLEBiological False +

ve STSVariety of AutoAbNucleiIntracytoplasmic cell constituentsThyroid & other organsLE cell- Neutrophils containing LE Bodies (large pale homogenous body) almost filling cytoplasmAntinuclear Ab (ANA)—Sensitive but not specificPattern: homogenous, Peripheral, speckled, nucleolarAnti DNA Ab- ds, ss, bothAnti-ds DNA Ab & Anti sm Ab---specific for SLE47

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THANK YOU

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