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

9. Tolerance and Autoimmunity

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

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

14. 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

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

17. 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

18. 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)

21. 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

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

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

26. 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

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

28. 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

29. 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

31. 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)

32. 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

33. 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

40. 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

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

42. Localised Organ Specific Ds

43. 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

44. 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

47. 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

60. THANK YOU