Autoimmunity in pathology

1. Autoimmunity

2. Autoimmune disorder?
Pre-requisites
Presence of an immune rxn specific
to a self-antigen/tissue
Immune rxn is not secondary to
tissue damage, but a primary
pathology
Absence of another well-defined
cause of the disease

4. Autoimmune disorders
• Organ-specific vs. generalised disorders*
• Results from loss of self-tolerance (lack of
responsiveness to one’s own Ag)!
• What is [immunologic] tolerance?
Unresponsiveness to an Ag due to
exposure of lymphocytes to that Ag

5. Self- tolerance
Central tolerance
AIRE(autoimmune regulator) is critical for deletion of immature self-reactive T-cells.

7. Peripheral tolerance
• Anergy – functionally unresponsive
✓ weak expression of costimulatory molecules on resting
APCs in normal tissue
✓ Coinhibitors /inhibitory receptors on T cells - CTLA4
binds to B7 and PD1 binds to PDL1/2
✓ Anergy also affects B cells on encountering self Ag – in
absence of specific helper T cells → unable to respond
to subsequent Ag stimulation → cell death
• Supression by regulatory T cell by secreting
immunosuppressive cytokines, IL10 & TGF b
• Deletion by apoptosis - Self reactive Bcells also deleted
by Fas L on T cells engaging with Fas on Bcells.

8. Peripheral tolerance
• Deletion by apoptosis –
✓Tcells recognize self Ags → proapoptotic Bim
→ apoptosis
✓Recognition of self Ag → lymphocytes express
Fas which binds to FasL on activated Tcells→
apoptosis
✓Self reactive Bcells also deleted by Fas L on T
cells engaging with Fas on Bcells.

9. Self- tolerance
Peripheral tolerance

10. Self- tolerance
Peripheral tolerance: Anergy & regulatory T cells
CTLA4
• High Bim; low Bcl-2/x
• Fas-Fas ligand

11. Self- tolerance
Peripheral tolerance: Suppression by
regulatory T cells
• Derived from Thymus
• Express CD25, IL-2 &
FOXP3* (CD4 cell
maintenance)
• Secrete IL-10 & TGF-β
(inhibit lymphocyte
activation)
• Express CTLA4*

12. Mechanisms of Autoimmunity
Lymphocyte
activation
Tolerance

13. Mechanisms of Autoimmunity
Lymphocyte
activation
Tolerance

14. Mechanisms of Autoimmunity
1. Inheritance of Susceptibility genes
(contribute to breakdown of self-
tolerance)
2. Role of Environmental triggers
(promote activation of self-reactive
lymphocytes)

15. Mechanisms of Autoimmunity
Susceptibility genes
▪ HLA alleles:
✓ B27 (ankylosing spondylitis)
✓ DRB1/2 (Rheumatoid arthritis)
▪ Non-HLA genes:
✓ PTPN22* (DM,RA)
✓ NOD-2 (Crohn disease)
✓ IL-2 & IL-7 receptors (MS)

16. 1. Infections may up-regulate expression of
co-stimulators on antigen-presenting cells
Environment: Role of infections

17. 2. Molecular mimicry: Microbes may express
antigens that have the same amino acid
sequences as self-antigens
Eg: RHD
Environment: Role of infections

18. 3. Epitope spreading: Infections and initial
autoimmune response, may structurally alter
self-antigens and expose epitopes of the
antigen that are normally concealed from
the immune system.
Environment: Role of infections

19. 4. Polyclonal B cell activation:
Eg: EBV & HIV: may produce autoab.
Environment: Role of infections

20. Mechanisms of Autoimmunity

21. Systemic Lupus
Erythematosus
(SLE)

22. SLE
• SLE is a complex disorder of multifactorial origin
from interactions among genetic, immunological
and environmental factors
• Tissue injury by autoantibodies (ANA*)
• Principal injury to the skin, joints, kidney &
serosal membranes
• Predominantly in women (F:M-9 : 1)

23. Hallmark feature
Autoantibodies!
• Antibodies against an array of
nuclear & cytoplasmic components
of the cell
• Diagnostic and pathogeneic
significance
• Role in management of pts

24. Antinuclear antibodies (ANA)
Ab to DNA
Ab to Histones
Ab to nucleolar
antigens
Ab to non histone
proteins bound to
RNA

25. Antinuclear antibodies (ANA)
Specificity of
AutoAb
% positive Association
Anti-dsDNA 40-60 Nephritis
Anti-U1-RNP 30-40
SLE-specific
Anti-Smith Ag 20-30
Anti-Ro(SS-A)/La
(SS-B)
30-50 Neonatal lupus,
congenital heart block
Anti-PL 30-40 APLA
Generic ANAs* 95-100 Not specific*

26. RIM HOMOGENOUS
SPECKLED NUCLEOLAR
SLE
DRUG
SYSTEMIC SCLEROSIS
Anti Sm
Staining patterns of ANAs

27. Antinuclear antibodies (ANA)
• Detected by Indirect Immunofluorescence
STAINING PATTERN ANTIBODIES AGAINST
➢ Homogenous or diffuse Chromatin, histones &
ds-DNA
➢ Rim or peripheral staining ds-DNA nuclear envelope
proteins
➢ Speckled Non-DNA nuclear constituents
like: Sm antigen,
ribonucleoprotein,
SS-A & SS-B
➢ Nucleolar Nucleolar RNA
➢ Centromeric pattern Centromeres (SS)

28. Other Autoantibodies in SLE
• vs. RBCs, platelets, lymphocytes
• Antiphospholipid antibodies(30-40%) – against
epitopes of plasma proteins revealed when
they complex with phospholipids
➢ may interfere with clotting tests like partial
thromboplastin time- lupus anticoagulant
➢Excessive clotting

29. Aetiopathogenesis
Immunologic
factors
Environmental
factors
Genetic
factors

30. Aetiopathogenesis
✓Family history (increased risk)
✓Monozygotic (20%) > dizygotic twins (1-3%)
✓MHC associations: HLA-DQ (anti-dsDNA, Sm)
✓Inherited def. of Complement (C2,C4, C1q)
- Impaired removal of IC, apoptotic cells by
macrophages: tissue injury
✓Genetic loci encoding proteins in lymphocyte
signaling
Genetic
factors

31. Aetiopathogenesis
✓ Breakdown in self-tolerance in B cells
✓ CD4+ helper T cells specific for nucleosomal
antigens* escape tolerance – B cells produce high
affinity auto Ab
✓ Toll-like receptors (TLR) engagement by DNA & RNA
in IC→ activated B cells > autoAb production
✓ Type 1 interferons (self nucleic acids mimic microbes
>IFN > activate B cells > autoAb production
Immunologic
factors

32. Aetiopathogenesis
✓ Exposure to UV light
– Induces apoptosis, alters DNA → enhanced
recognition by TLR- immunogenic
– Production of IL-1 : inflammation +
✓Gender predisposition:
Sex hormones (X chr genes)
✓Drugs: d-penicillamine, hydralazine, procainamide
Environmental
factors

33. A model for pathogenesis of SLE

35. CRITERIA FOR DIAGNOSIS OF SLE
Proposed in 1997 and updated in
2012.
4 of the clinical and immunological criteria to
be met at any time with atleast 1 clinical and 1
immunologic criteria*

37. M-Malar rash
D- Discoid rash
S- Serositis
O- Oral ulcers
A-Arthritis
P-Photosensitivity
B-Blood abnormalities
R- Renal
A- ANA antibodies
I- Immune abnormalities
N-Neurologic

38. Mechanisms of tissue injury in SLE

39. Mechanisms of tissue injury
1. Type III hypersensitivity:systemic lesions
– Immune complex deposition + low complement
levels

40. Mechanisms of tissue injury
Damaged cell nuclei bind to ANA >> lose their
chromatin & become homogeneous
Lupus erythematosus (LE) or hematoxylin bodies
LE cell is a phagocytic leukocyte (neutrophil &
macrophage) that has engulfed denatured nucleus of
an injured cell- seen when blood is agitated in vitro

41. LE cell

42. Mechanisms of tissue injury
2. Autoantibodies against RBC, WBC & platelets
opsonize these cells & promote their phagocytosis &
lysis → Type II hypersensitivity reaction
ITP

43. Mechanisms of tissue injury
3. Antiphospholipid Antibody Syndrome (APLA)
• Venous and arterial thrombosis
• Ab vs endothelium, platelets, clotting factors
4. Neuropsychiatric manifestations – Ab cross the
blood brain barrier and react with neurons.

44. Morphological changes in SLE

45. Blood vessels – acute necrotizing vasculitis with
fibrinoid necrosis in any tissue
➢Capillaries, arteries and arterioles
➢Chronic – fibrous thickening with luminal
narrowing

46. Skin:
• Malar rash, butterfly rash → face (50%),
trunk, extremities
• Urticaria, bullae, maculopapular rash, ulcers
• Exposure to sunlight incites or accentuates
the erythema
• Histology:
– Vacuolar degeneration of basal layer
– Dermal edema
– Vasculitis with fibrinoid necrosis

47. Malar rash
Butterfly shape

48. 2. Discoid rash

49. • Liquefactive
degeneration &
edema
• IgG and complement
deposits along the
dermoepidermal
junction

50. Other organs
• Joints- Non erosive synovitis
• Spleen: Capsular thickening, follicular hyperplasia
and “Onion skin” lesions involving central penicilliary
arteries
• CNS- vasculitis or non inflammatory occlusion of
small vessels by intimal proliferation
• Pericarditis and serosal cavity involvement- covered
with fibrinous exudate; later becomes fibrotic &
obliterates the serosal cavity

51. Cardiovascular system:
• Pericarditis
• Myocarditis
• Diffuse valve thickening –mitral and aortic valve
• Valvular endocarditis: Libman-Sacks
endocarditis or nonbacterial verrucous
endocarditis – multiple, irregular, 1-3mm warty
deposits on either surface of leaflets
• Coronary artery disease → esp in young
patients with long standing disease

52. KIDNEY: Morphological Classification*
Class I : Minimal mesangial
Class II : Mesangial proliferative
Class III : Focal lupus nephritis(<50%)
Class IV : Diffuse proliferative (>50%)
Class V : Membranous LN
Class VI : Advanced sclerosing
Tubulointerstitial lesions

53. Normal Glomerulus

54. Class I: Minimal Mesangial
• Immune complex deposition in mesangium
• Identified by IF

55. Class II : Mesangial proliferative
❖Mild hematuria ,transient
proteinuria
❖Slight ↑ in mesangial matrix & cells
❖IF : granular mesangial deposits of Ig
& C

56. Class III : Focal lupus nephritis
➢<50% glomeruli
➢Segmental/global
➢1-2 tufts show
↑endothelial, mesangial
and inflammatory cells,
fibrinoid dep, hyaline
thrombi
➢Focal necrotising lesions,
crescents
➢Mild hematuria
&proteinuria

57. Class IV : Diffuse Lupus Nephritis
▪ >50% of glomeruli affected
▪ Glomeruli: hypercellular, crescents, fibrinoid
necrosis, leukocytes, apoptotic bodies, hyaline
thrombi
▪ Subendothelial immune complex deposition
“Wire loop lesions”
▪ Hematuria, proteinuria, HTN, renal insufficiency

58. Diffuse proliferative lupus nephritis

59. IgG deposits in Diffuse proliferative lupus
nephritis

60. Wire-loop lesions (PAS)

61. Class V : Membranous GN
– Widespread thickening of capillary walls
(subepithelial IC deposits) + BM material
deposition
– Nephrotic syndrome

62. CLASS VI : Advanced Sclerosing lupus
nephritis
• Sclerosis of >90% glomeruli
• End-stage renal disease