This document discusses autoimmune disorders and the role of autoantibodies. It begins by outlining the spectrum of autoimmune disorders and how the immune system can fail, leading to autoimmune responses. It then discusses the levels of self-reactivity and autoimmunity, from normal to pathological. Key points include that autoantibodies can directly or indirectly cause tissue damage in various disorders, and that defects in central and peripheral tolerance can lead to a loss of self-tolerance. The document also examines evidence of autoimmunity, molecular mimicry, and the clinical manifestations of various autoimmune diseases.

1. AUTOIMMUNITY
and
related Disorders
part 2
Dr Abhirup Chatterjee
MBBS MD(Medicine)
R G Kar MCH

2. Spectrum of autoimmune
disorders

3. • What are various of auto-immune disorders?
• How this complex immune system fails, and
auto-immune response ensues?
• How auto-Abs are damaging? (and helpful?)
• Why women are more susceptible than men?

4. FROM ‘HORROR AUTOTOXICUS’ TO…
‘Physiologic’
level of ‘self-
reactivity’
‘Intermediate’
level of
autoimmunity
‘Pathological’
level of
autoimmunity

5. HSC
CMP
Erythroid Myeloid
Granulo Myeloid
APCs
(Mono/
Mɸ/
Dendritic)
CLP
NK B T
Th
Th1 Th2 Treg Th17
Tc
INNATE IMMUNITY ACQUIRED IMMUNITY
INNATE
AUTO-
INFLAMMAT
ORY
DISEASES
OVERLAP
-Behcet’s
-SoJIA
-CD
ADAPTIVE
AUTO-
IMMUNE
DISEASES

7. So what goes wrong?

8. Evidence of Autoimmunity
•Transfer of auto-Ab into animal models
•human-to human transfer/ vertical transmission
•In vitro transfer
DIRECT
direct cause-effect
relationship
•Produce disease in animal model
•Naturally occurring disease with human analogy
•Disease d/t manipulation of immune system
INDIRECT
indirect cause-
effect relationship
•Cluster of AIDs
•HLA cluster
•Gender bias
•Response to immunosuppressant
CIRCUMSTANTIAL

9. Breach in Tolerance
SELF-TOLERANCE/TOLERANCE
CENTRAL
NEGATIVE
SELECTION
RECEPTOR
EDITING
PERIPHERAL
COSTIMULATORY
SIGNAL
B-cell Tolerance
REGULATORY T-CELL/
TReg
•AIRE: APS 1,
•ZAP-70: Inflm Arthritis
•SLE, RA: auto reactive
B-cell
•FAS-FASL : ALPS
•FOXP3: IPEX

10. Loss of tolerance due to
genetically imposed defects in
Central and peripheral
tolerance
Conventional Immune response
to self-Ag for which tolerance is
normally incompletely
established
SYSTEMIC AIDs ORGAN SPECIFIC AIDs

11. Basic pathogenesis of all AIDs
Activation and
expansion of
naïve
autoreactive
lymphocytes
Innate
inflammatory
factor
Co-
stimulating
factor
Epitope spreading and activation of an
expanding repertoire of self reacting
lymphocytes recognizing auto Ag beyond
the initiating one
Production of
neo-self Ag
-Citrulinated
proteins
-Immune
complexes eg.
Rheumatoid
factor and
-Type 4
collagen in
Good Pasteur
Molecular
mimicry
-cardiac myosin
with NAG and
M-protein of
Grp A Strepto
-C jejuni LOS
with GM1 in
AMAN-GBS

12. Molecular Mimicry

13. A complex interaction

14. Clinical manifestations of AIDs
Pathogenic effect of auto-Abs
• Blood cells- AIHA, ITP, APLS
• Thyroid- Graves’, Hashimoto
• Muscle and Nerves- GBS,
LEMS, MG, MS
• Stomach- Pernicious An
• Intestine- Celiac
• Skin- Pemphigus
• GBM- Anti-GBM
• Sperm- Infertility
• Heart- Congenital CHB
Pathogenic effect of immune
complexes
• Lupus Nephritis
• Joint destruction and
nodules in RA
• Skin rash in vasculitis
• AAV related
Glomerulonephritis

15. Auto-Abs in various AIDs

17. Antinuclear antibody
• Testing of individual ANA
specificities should be
performed only in the
context of clinical signs that
correlate with antibody-
disease associations (e.g.,
anti-DNA or anti-Smith [Sm]
in the suspicion of SLE).
• It adds weight to diagnoses
that rely heavily on other
clinical information.

18. ANA specificities in SLE
• Anti–double stranded DNA, which corresponds
to renal disease and overall disease activity;
sensitivity around 70%
• Antiribosomal P, which corresponds to
neuropsychiatric manifestations and renal
disease;
• Anti-Ro/SS-A and anti-La/SS-B, which associate
with cutaneous and neonatal lupus; and
• Anti-Sm, which is considered highly SLE specific
without clear clinical disease manifestation
correlations; sensitivity around 30-40%

19. ANA specificities in systemic sclerosis
• Antikinetochore (anti-centromere), which
corresponds to CREST(calcinosis, Raynaud’s
phenomenon, esophageal dysmotility,
sclerodactyly, and telangiectasias) manifestations,
PAH and PBC; specificity 95%, sensitivity 30-60%
• Anti–sclerosis (Scl)-70 (topoisomerase I) and
anti–RNA polymerase III, which are associated
with diffuse cutaneous disease and pulmonary
fibrosis, and accelerated risk of cancer-associated
systemic sclerosis, almost 100% specific; and
• Anti–polymyositis (PM)-Scl (exosome), which is
found in myositis–systemic sclerosis overlap.

20. ANA specificities in Sjögren’s syndrome
(SS) include
• Anti-Ro/SS-A and anti-La/SS-B, found in
mothers of children with neonatal lupus, and
• Antifodrin, which does not seem to have well-
documented prognostic ramifications, but,
similar to anti-Ro/SS-A and anti-La/SS-B, is
observed at high frequency in the disease.
• Rheumatoid factor: up to 74% cases of SS

21. ANA specificities in inflammatory
myositis
• Anti-synthetase, such as antihistidyl transfer
RNA synthetase (e.g., Jo-1), which is
associated with the poor-prognosis, Anti-
synthetase syndrome, and
• Anti–Mi-2 (nucleosome remodeling-
deacetylase complex), which is associated
with dermatologic manifestations

22. Anti-Phospholipid Abs
• Beta2 GP1 dependent aPL:
-Anti-beta2GP1 [IgG, IgM (and IgA, not in APLS criteria)]
-Anti-cardiolipin Ab [IgG, IgM (and IgA, not in APLS
criteria)]
-Lupus anticoagulant
• Beta2GP1 independent aPL:
-infections eg. Treponemes, Lyme’s, HIV, Leptospira,
parasites
-drugs- quinidine, procainamide, CPZ, phenytoin
-lymphoproliferative malignancies
• Normal : role in physiologic removal of oxidised lipids

23. Auto-immunity in RA
• Genetic: HLA DR4, PTPN22, PADI4
• Smoking and tobacco products:↑Citrullination
• Silica dust
• Diet and obesity- ↑Adipokines
• Infection: EBV, Parvo, Mycoplasma, MTb, Porphyromonus gingivalis,
Prevotella copri
• Gender: F:M=2:1 to 3:1
• Pregnancy: remission in 3rd Tm, 90% flares in PP
• Auto-Ab:
-Rheumatoid factor: IgG, sensitivity=60-90%, specificity=85%
-ACPA: Specificity 95-98%, 70-80% sensitive, marker of severity, early
predictor, may precede joint damage;
-Anti-carbamoylated protein Ab/ ACarPs: (+)in 30% ACPA (-) pts;
-Anti-PAD4
-Anti-MAA Ab

24. Auto-Abs in AAV
• c-ANCA (major Ag PR3): GPA (90%)
• p-ANCA (major Ag MPO, other cathepsin,
lactoferrin,elastase etc) :
-microscopic polyangiitis,
-EGPA,
-isolated necrotising crescentic glomerulonephritis,
-[non MPO p-ANCA in] IBD (UC>CD), PSC, type I AIH, IE,
bacterial infection in cystic fibrosis pts, Minocycline
induced vasculitis, cocaine induced destructive midline
injury [elastase],
-sometimes PAN
• Anti LAMP-2

25. Graves’ disease
• 1. Gene: HLA DR3,CD40, PTPN22, CTLA-4, FCRL3
• 2. Infection: Yersinia enterocolytica, cag-A (+)
H.pylori
• 3. Gender: F>M
• 4. smoking: increased r/o TAO, relapse
• 5. Vitamin D and Selenium deficiency
• Auto-Abs : TSH-R (sensitivity: 75-95%, specificity:
99%); TRAB: a. TSAb [LATS], b. TBAb
• Other auto-Ab : -Tg, TPO
-TAO: IGF-1R

26. Hashimoto Thyroiditis
• 1. Gene: HLA, CTLA-4, PTPN22
• 2. Smoking
• 3. Iodine,Selenium
• 4. Drugs: Amiodarone, Lithium, IL-2, GM-CSF, HAART
• 5. Pregnancy and puerperium
• Auto-Abs: a) Anti-Tg: in 60% cases; IgG4
b) Anti-TPO: high affinity IgG Ab, major role, 95%
confirmatory, positive in >90% cases
c) TSBAb: found in both goitrous and atrophic thyroiditis
( TSBAb TSAb )
d) others: anti-NIS, anti-T3/T4, anti-colloid Ag-2, anti-cell
surface Ag (unknown role in pathogenesis)

27. Auto-Abs in neurological diseases
• Myasthenia Gravis: Anti-AChR (IgG4), Anti-MusK
(IgG), anti-Lrp3
• LEMS: P/Q type VGCC (IgG)
• MS: Against kir4.1, MBP (myelin bsic protein), PLP
(myelin proteolipid), gangliosides, Neurofascin
• GB syndrome: GM1, GQ1b, GD1b, GT1a,
contactin; Miller-Fischer variant: GQ1b (IgG)
• Autoimmune encephalitis: anti-NMDAR Ab
• NMO: AQP4 and myelin oligodendrocyte
glycoprotein/MOG

28. Type 1 Diabetes Mellitus
• 1. Islet cell Ab :
- GAD-65: 70-80% in new onset type 1 diabetes
- IA-2 (Islet Ag 2): Tyrosine Phosphatase (IA-2,
IA-2beta)
- Anti Insulin Ab : 50% among new type 1 DM
- ZnT8 Transporter
• 2. others: Thyroid (TPO, Tg), stomach, Adrenal,
nucleic acid, albumin

29. And a few others…
• Celiac disease
1. Anti-TTG: IgA subtype; 5% are IgA deficient, l/t false (-)
2. Anti-Gliadin
3. Anti-endomysial Ab
• Pernicious Anemia
1. Anti parietal cell Ab
2. Intrinsic factor binding Ab
• Vitiligo
1. Anti-melanocyte Ab
2. Anti-Tyrosinase Ab
3. Tyrosine related protein-1
4. Aromatic l-amino acid decarboxylase
5. Transcription factor SOX9, SOX10

30. Why women are more commonly
affected?
• Differential immune response in two sexes
• Influence of sex hormones
• Pregnancy and AIDs

31. TO BE CONTINUED…