1. Autoimmunity
Dr K V CHAKRADHAR
ASSISTANT PROFESSOR,
DEPARTMENT OF MICROBIOLOGY,
NRIIMS.

2. What is Autoimmunity?
 Activation of an immune response against self-tissue
 Specific breakdown of mechanisms responsible for
tolerance to self-antigens

3. History
 Discovery and rediscovery of autoimmunity
 Ehrlich (1901)- Horror autotoxicus
 Julius Donath and Karl Landsteiner (1904) – PKH
 Ernest Witebsky (1950)- Demonstrated the induction of
autoimmunity in an animal model of chronic thyroiditis

4. Proposed mechanisms of immunity

5. Sequestered
antigen
Polyclonal B-cell
activation
Loss of suppressor
cells
Escape of auto reactive clones
Proposed mechanisms for induction of immunity
Cross reactive
antigens
Altered self antigens

7. Sequestered antigen
 Late-developing antigens or may be confined to
specialized organs (e.g., testes, brain, eye, etc.).
 Accidental traumatic injury or surgery,
 Initiation of an autoimmune disease.

8. Damage to immunologically
privileged sites can lead to
autoimmunity

9. Escape of auto-reactive clones
 The negative selection in the thymus may not be fully
functional to eliminate self reactive cells.
 Not all self antigens may be represented in the thymus or
certain antigens may not be properly processed and
presented.

10. Lack of regulatory T cells
 There are fewer regulatory T-cells in many autoimmune
diseases.

11. Cross reactive antigens

Post streptococcal nephritis and carditis (Rheumatic
fever)

Anticardiolipin antibodies during syphilis

Association
spondylitis.

Molecular mimicry – homologous sequences are seen
between Klebsiella and ankylosing

Arthritogenic Shigella flexneri and HLA-B27

Mycobacterium tuberculosis and

Joint membranes, Coxsackie B and myocardium.

12. Antigenic alteration
 This is due to physical, chemical, biological influences.
(Radiation, light, cold, drugs, viral infections)

13. Polyclonal B activation
 Gram-negative bacteria- endotoxin (LPS) ,
Cytomegalovirus (CMV), and Epstein-Barr virus
(EBV).

14. Interplaying factors

15. Genetic Factors

16. Genetic predisposition for
autoimmunity
 Association between certain HLA types and
autoimmune diseases has been noted (HLA: B8,
B27, DR2, DR3, DR4, DR5 etc.).

17. Many autoimmune diseases are associated with certain
HLA types and with gender

18. Environmental
Factors

19. Diseases
Pathogen
Grave’s disease
Yersinia enterocolitica
Immune haemolytic anaemia
Epstein-Barr virus, Mycoplasma pneumoniae
Kawasaki disease
Staphylococcus aureus, Streptococci,
Yersinia pseudotuberculosis
Henoch-Schoenlein purpura
β-hemolytic Streptococcus
Rheumatoid arthritis
Mycobacterium tuberculosis
Polyarteritis nodosa
Hepatitis B and C viruses, Human
Immunodeficiency virus
Spondylarthropathies
Enterobacteriacae,. Klebsiella spp.
Reiter’s disease
Enterobacteriacae, Chlamydia trachomatis
Systemic lupus erythematosus
Retroviruses
Crohn’s disease
Mycobacterium paratuberculosis
Celiac disease
Adenoviruses
Psoriasis
Retroviruses, Streptococci

20. Occupational and other exposures
associated with autoimmune disease
Exposure
Disease
Silica
Systemic sclerosis, SLE, RA
Solvents
Systemic sclerosis, Multiple sclerosis, RA
Pesticides
RA
UV radiation
Multiple sclerosis, Dermatomyositis
Cigarette smoking
RA, Autoimmune thyroid disease

21. Gender predominance in autoimmune
diseases

22. Types of Autoimmune diseases
 Classified on the basis of:
Organ specificity and Systemic diseases
Based on pathogenic organisms
Based on type of hypersensitivity reaction

23. Organ specific and Systemic
autoimmune diseases

24. Disease
Self-antigen
Immune response
ORGAN SPECIFIC AUTOIMMUNE DISEASE
Addison’s disease
Adrenal cells
Auto-antibodies
Autoimmune hemolytic RBC membrane proteins
anaemia
Auto-antibodies
Goodpasture’s
syndrome
Renal and lung basement
membranes
Auto-antibodies
Hashimoto’s thyroiditis
Thyroid protein and cells
TDTH cell auto-antibodies
ITP
Platelet membrane
peoteins
Auto-antibodies
IDDM
Pancreatic β-cells
TDTH cell auto-antibodies
Myasthenia gravis
Acetylcholine receptor
Auto-antibodies
(blocking)
Pernicious anaemia
Gastric parietal cells,
Intrinsic factor
Auto-antibodies
PSGN
Kidney
Ag-Ab complex
Spontaneous infertility
Sperm
Auto-antibodies

25. Disease
Self-antigen
Immune response
SYSTEMIC AUTOIMMUNE DISEASES
Ankylosing spondylitis
Vertebrae
Immune complexes
Multiple sclerosis
Brain or white matter
TH1 cell and Tc cells,
auto-antibodies
RA
Connective tissue, IgG
Auto-antibodies, Immune
complexes
Scleroderma
Nuclei, heart, lungs, GI
tract, Kidney
Auto-antibodies
Sjogren’s syndrome
Salivary gland, liver,
lacrimal gland, kidney
Auto-antibodies
SLE
DNA, nuclear pattern,
RBC and platelet
membranes
Auto-antibodies, Immune
complexes

26. Based on pathogenic organisms

27. Disease
Pathogen
Host self-antigen
Rheumatic fever
Group A Streptococci
Cardiac myosin
Guillain –Barre syndrome
Campylobacter jejuni
Peripheral nerve
ganglioside proteins
Treatment-resistant Lyme
arthritis
Borrelia burgdorferi
LFA-1
Myocarditis
Group B Coxsackie virus
Cardiac antigens
Chagas’ disease
Trypanosoma cruzi
Cardiac myosin heavy
chain
Herpetic stromal keratitis
Herpes simplex virus
Corneal antigen and
IgG2a
Type 1 diabetes
Group B Coxsackie virus
Glutamate
decarboxylase
Myasthenia gravis
Herpes simplex virus
Acetylcholine receptor
Multiple sclerosis
Epstein Barr virus (EBV)
Myelin basic protein

28. Diseases
Pathogen
Grave’s disease
Y. enterocolitica
Immune haemolytic anaemia
Epstein-Barr virus, Mycoplasma pneumoniae
Kawasaki disease
Staphylococcus aureus, Streptococci,
Yersinia pseudotuberculosis
Henoch-Schoenlein purpura
β-hemolytic Streptococcus
Rheumatoid arthritis
Mycobacterium tuberculosis
Polyarteritis nodosa
Hepatitis B and C viruses, Human
Immunodeficiency virus
Spondylarthropathies
Enterobacteriacae,. Klebsiella spp.
Reiter’s disease
Enterobacteriacae, Chlamydia trachomatis
Systemic lupus erythematosus
Retroviruses
Crohn’s disease
Mycobacterium paratuberculosis
Celiac disease
Adenoviruses
Psoriasis
Retroviruses, Streptococci

29. Based on type of Hypersensitivity
reaction

30.  Type II hypersensitivity reaction (antibodies to cell
surface molecules)
Disease
Auto-antigen
Outcome
Autoimmune hemolytic
anaemia
Rh blood group antigens
Lysis of RBC by
complement and FcR+
cells→ Anaemia
Autoimmune
thrombocytopenic
purpura
Platelet integrin:
GpIIb/IIIa
Abnormal bleeding
Goodpasture’s syndrome
Basement membrane
type IV collagen
Glomerulonephritis,
pulmonary haemorrhage
Grave’s disease
TSH receptor
Thyroid overactivity
Hashimoto’s thyroiditis
Thyroglobulin, thyroid
peroxidase
Thyroid underactivity
Hypoglycemia
Insulin receptor (agonist)
Low blood glucose

31. Disease
Autoantigen
Outcome
Insulin resistant diabetes
Insulin receptor
(antagonist)
High blood glucose,
Ketoacidosis
Myasthenia gravis
A chain of nicotinic
acetylcholine receptor
Progressive weakness
Pemphigus vulgaris
Epidermal cadherin
Skin blisters
Pernicious anaemia
Intrinsic factor, Gastric
parietal cell
Anaemia
Rheumatic fever
Streptococcal cell wall
antigens, antibodies
cross react with heart
muscles
Arthritis, myocarditis,
heart valve scars
Spontaneous infertility
Sperm antigens
Infertility

32. Graves’ disease (antithyroid stimulating hormone
receptor {TSHR} antibodies)

34. Myasthenia gravis
(anti-acetylcholine receptor
antibodies)

35.  Type III: Immune complex disease
Disease
Autoantigen
Outcome
Ankylosing spondylitis
Immune complexes
Damage to vertebra
Mixed essential
cryoglobulinemia
Rheumatoid factor,
IgG complexes
Arthritis
SLE
DNA, histones,
ribosomes, smRNP,
scRNP
Glomerulonephritis,
vasculitis, rash

37.  Type IV: T cell-mediated disease
Disease
Auto-antigen
Outcome
Multiple sclerosis
Myelin
oligodendrocyte
glycoprotein
Brain invasivion by
CD4 cells, weakness
Hashimoto’s thyroiditis Thyroid antigen
Thyroid underactivity
IDDM
Pancreatic β-cell
antigen
Β-cell destruction
RA
Unknown synovial
joint antigen
Joint inflammation
and destruction

38. Joint deformity in Rheumatoid arthritis

39. In insulin-dependent
diabetes mellitus,
cytotoxic T-cell kill the
cells (cells that make
insulin)
Insulin is
stained brown

40. Aetiopathogenesis
 Mechanism preventing autoimmunity- “IMMUNOLOGICAL
TOLERANCE”
 Broadly divided into two groups:
1. Central tolerance
2. Peripheral tolerance
 Anergy
 Suppression by regulatory T cells
 T-cell ignorance
 Antigen sequestration

41. Laboratory diagnosis

42. Routine investigations asked for
diagnosis for Autoimmune diseases:
 Complete blood count
 Peripheral smear
 Synovial fluid analysis
 RFT
 LFT
 Urine analysis
 Radiological investigations- X-ray, Ultrasound, MRI, CT
scan
 Histopathological examination of affected

43. Laboratory diagnosis
 Auto-antibodies
Antinuclear antibodies (ANA)
Antineutrophil Cytoplasmic Antibody (ANCA)
Rheumatoid factor
 Acute phase proteins
 HLA typing
 ASO titer

44. AUTO ANTIBODIES

45. Antinuclear antibodies
 Initially discovered in the 1940s using the LE cell test
 LE cell test: lacks sensitivity, specificity and predictive value
 Nowadays used: Immunofluorescence anti-nuclear
antibody test (IF-ANA) and EIA/ELISA
 Flow cytometry and nanotechnology
 Method of choice: Indirect immunofluorescence (IMF) using
cultured Hep2 cells

46. Interpretation
 ANA with titer, in combination with a full history and
physical examination, extremely useful in the diagnosis
and exclusion of connective tissue disease
 Titer >1:640 should increase the suspicion
 Titer <1:80 and no or few signs or symptoms of disease much smaller likelihood

47. ANA HOMOGENOUS – HEP2010

48. ANA NUCLOPLASM GRANULAR – HEP
2010

49. ANA CYTOPLASM GRANULAR;Jo 1 HEP 2010

50. ANA CYTOPLASM GRANULAR;GOLGI
APPARATUS - HEP 2010

51. ANA NUCLEOLI POSITIVE
– HEP 2010

52. ANA NUCLEAR DOTTED
– HEP 2010

53. cANCA – ETHANOL FIXED
GRANULOCYTES

54. pANCA – ETHANOL FIXED
GRANULOCYTES

55. Autoimmune disease
Sensitivity (%)
Systemic lupus erythematosus
95-100
Scleroderma
60-80
Mixed connective tissue disease
100
Polymyositis/dermatomyositis
61
Rheumatoid arthritis
52
Rheumatoid vasculitis
30-50
Sjögren's syndrome
40-70
Drug-induced lupus
100
Discoid lupus
15
Pauciarticular juvenile chronic arthritis
71

56. Non-rheumatic disease
Hashimoto's thyroiditis
46
Graves' disease
50
Autoimmune hepatitis
100
Primary autoimmune cholangitis
100
Primary pulmonary hypertension
40

57. Acute phase reactants

58. Acute phase proteins
 Those proteins whose plasma concentration changes by
at least 25% during inflammatory states
 Occurs in association with infection, trauma, inflammatory
arthritis, neoplasms.
 Positive reactants/negative reactants
 Most widely used – ESR, CRP

60. Conditions associated with increased
CRP
 Insignificant elevation (<1mg/dL)
 Exercise, flu, pregnancy, gingivitis, CVA, seizures,
angina
 Moderate elevation
(1-10mg/dL)
 MI, malignancy, pancreatitis, mucosal infection, most
rheumatic diseases
 Marked elevation
(>10mg/dL)
 Acute Bacterial infection, major trauma, systemic
vasculitis

61. Rheumatoid Factor
 Antibodies directed against Fc portion of IgG
 IgM RF usually measured
 Detected by
 Agglutination of IgG-sensitized sheep red cells
 Bentonite or latex particles coated with human IgG
 RIA
 ELISA
 Nephelometry

62. RF in rheumatic diseases
 Rheumatoid arthritis: 26-90%
 Sjögren's syndrome: 75-95%
 Mixed connective tissue disease: 50-60%
 Mixed cryoglobulinemia (types II and III): 40-100%
 Systemic lupus erythematosus: 15-35%
 Polymyositis/dermatomyositis: 5-10%

63. Rheumatoid factor titer
 Higher the titer greater the likelihood of rheumatic
disease
 Prognostic value in RA

64. Treatment
A) Symptomatic
 Anti-inflammatory drugs: SLE, RA
 Plasmapheresis: SLE, Guillain-Barre
 Splenectomy : ITP
 Anticholinesterase and thymectomy: Myasthenia gravis
 Hormone replacement: Hashimoto thyroiditis, type I diabetes
B) Immunosuppressive Agents:
 Two Categories
1. Lympholytic: Ionizing radiation; Antiserums-Antilymphocyte
serum, Antithymocyte serum, Anti-RhD
2. Lymphocytotoxic : Antimetabolites, Alkylating agents