Disorders of Immunity - 4Autoimmunity

Dr.CSBR.Prasad, M.D.

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Autoimmune diseasesAutoimmune diseasesImmune reaction against self antigen

DEFINITION

Autoimmunity can be defined as breakdown of mechanisms responsible for self tolerance and induction of an immune response against components of the self.

Such an immune response may not always be harmful (e.g., anti-idiotype antibodies).

However, in numerous autoimmune diseases it is well recognized that products of the immune system cause damage to the self.

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Pathogenesis of autoimmune diseases

1Sex is a key factor in autoimmune disease, ie a number of autoimmune diseases are much more common in women than in men.

2There is a genetic background to autoimmune diseases and a strong correlation with particular MHC haplotypes. MHC associations differ in different ehtnic groups.

3T helper cells play a major role in autoimmunity through TH1 clones triggering a DTH response. Auto-reactive cytotoxic T cells develop more rarely but are found in IDDM.

4At least in experimental models and in certain human auto-immune diseases somatic hypermutation is an important process leading to auto-reactive antibodies.

5Infection by viruses (HCMV, EBV) or bacteria results in polyclonal B cell activation. This may constitute a mechanism for activation of anergic, self reactive B clones.

6 Exposure of segregated antigens can lead to autoimmune diseases.

7Molecular mimicry, ie the sharing of identical are highly similar antigenic determinants between viral /bacterial antigens and self antigens, plays little if any role in autoimmunity.APR-2015-CSBRP

Regulatory T cellsRegulatory T cells• Regulatory T cells (Formerly called suppressor cells)• Express CD4+ and CD25+. • They express forkhead family transcription factor Foxp3.

Expression of Foxp3 is required for regulatory T cell development and function.

• They supress immune activation by the production of immunosuppressive cytokines such as TGF-β and IL-10.

• Genetic mutations in Foxp3 in humans leads to development of a severe and rapidly fatal autoimmune disorder known as Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome.

• This disease provides the most striking evidence that regulatory T cells play a critical role in preventing autoimmune disease.

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Some notable pointsSome notable points• AI diseases are more common in females (75% of pts)• Autoantibodies appears normally with increasing age• Hypergammaglobulnemia is usually present• Autoantibodies against Adrenals, Parathyroids,

Pancreatic islets and mitochondria are uncommon at any age

• There is strong genetic predisposition• There may be familial clustering of AID• A patient with one type of organ specific AID is quite

likely to develop another**• The course of AID is variable and not always progressive

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Autoimmune Disorders

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Systemic Lupus Erythematosis - SLE

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Systemic Lupus Erythematosis

• Autoimmune disease• Multisystem affection• Characterized by presence of Antinuclear

Antibodies (ANA)• Acute or insidious in onset• Chronic remitting & relapsing febrile illness• Principally affects skin, joints, kidney &

serosal membrane

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Systemic Lupus Erythematosis

• American Rheumatism Association• 1997 revised 11 criteria for SLE

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SLE – 1997 Revised criteria

1. Malar rash – Fixed erythema over malar eminence2. Discoid rash – Erythematous raised patches with

adherent keratotic scaling & follicular plugging3. Photosensitivity – Skin rash after UV light exposure4. Oral ulcers –Painless oral / nasopharyngeal ulcers5. Arthritis – Non-erosive arthritis involving 2 or more

joints6. Serositis – Pleuritis / Pericarditis7. Renal disorder – Persistent proteinuria >0.5 g/dl

Cellular cast

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SLE – 1997 Revised criteria8. Neurological disorder – Seizures, Psychosis9. Hematological disorder

Hemolytic anemia with reticulocytosisLeukopenia < 4000/mm3Lymphopenia <1500/mm3Thrombocytopenia <1.0 lakh /mm3

10. Immunological disorderAnti–dsDNA, anti–sm & / or antiphospholipid

11. Antinuclear antibody (ANA)Abnormal titre of ANA in the absence of drug induced

SLE

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Other antibodies

Antinuclear antibody (ANA)Anti - ds DNA, Anti - ss DNAAnti – Sm AgAnti ribonucleoprotiens( anti RNA)Anti histone antibodies Anti-Nucleolar antibodiesAntiphospholipid antibodies

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Diagnosis of SLE

A person is said to have SLE if any 4 or more of the 11 criteria are present serially or simultaneously during any interval of observation

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Systemic Lupus Erythematosis

Etiology & pathogenesisFailure of self tolerance mechanisms1.Genetic factors2.Environmental factors3.Immunological mechanism

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Systemic Lupus Erythematosis

Genetic factors• Family members have increased risk of

developing SLE• Upto 20 % of clinically unaffected I0 relatives

show ANA• High rate of concordance in monozygotic

twins• MHC genes regulate production of auto-Ab

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Systemic Lupus ErythematosisEnvironmental factors• Drugs

• Hydralazine, • Procainamide, • D-Pencillamine can induce SLE like lesions

• UV light – exacerbate the disease

• Sex hormones – SLE 10x more common in females than males

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Systemic Lupus ErythematosisImmunological factors• Suppression of regulatory T cells • Inherited defect in B cells• Most of visceral lesions – Type III reactions• Auto antibodies against red cells, WBC &

platelet mediate their effect by -Type II reaction

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SLE – Clinical features & pathologic manifestation

• Hematologic – 100 %• Arthritis – 90%• Skin – 85%• Fever – 83%• Fatigue – 81%• Weight loss – 63%• Renal – 50%• CNS – 50%• Pleuritis – 46%• Pericarditis – 33%

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SLE - Morphology

• Immune complex disease – Blood vessel, kidney, connective tissue & skin

• Acute necrotizing vasculitis – small vessels & arterioles

• Chronic stage – fibrous thickening with luminal narrowing

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SLE - KidneySLE - Kidney

All SLE patient show lesion in kidney

WHO – 5 types of lupus nephritis• Class I –Normal by light M/s, EM & IF• Class II – Mesangial lupus GN• Class III – Focal proliferative GN• Class IV – Diffuse proliferative GN• Class V - Membranous GN• Class VI – Sclerosing nephropathy

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Mesangial lupus GN

• Increase in mesangial matrix & cells• Granular mesangial deposits of Ig &

complement are always present

• Mild hematuria/transient proteinuria

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Focal proliferative GN

• Focal lesion, affecting less than 50 % of the glomeruli

• Swelling & proliferation of endothelial & mesangial cells

• Neutrophils• Fibrinoid deposits & intra capillary thrombi

• Hematuria & proteinuriaAPR-2015-CSBRP

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Diffuse proliferative GN

• Proliferation of endothelial, mesangial cells & epithelial cells producing epithelial crescent

• Fibrinoid necrosis & leukocyte infiltration• Most or all glomeruli are involved

• Gross hematuria & proteinuria• Nephrotic syndrome – 50%

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Figure 20-16  Acute proliferative glomerulonephritis. A, Normal glomerulus. B, Glomerular hypercellularity is due to intracapillary leukocytes and proliferation of intrinsic glomerular cells. C, Typical electron-dense subepithelial "hump" and a neutrophil in the lumen.  

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Membranous GN

• Thickening of capillary wall

• Severe proteinuria - nephrotic syndrome

• EM – subepithelial deposits of immune complex

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SLE - SKIN

• Malar rash – 50-60% cases

• Liquefactive degeneration of basal layer• Edema, perivascular infiltrate• Vasculitis & fibrinoid necrosis of vessels• Ig & complement deposition along dermo-

epidermal junction

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Neonatal Lupus

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SLE - Joints

• Non erosive synovitis with little deformity• Neutrophilic infiltration & fibrin –

synovium• Perivascular mononuclear infiltrate in

subsynovial tissue

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SLE - CVSSLE - CVS

• Vegetations on tricuspid & mitral valve – Libman- Sacks endocarditis

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Diagnosis of SLEDiagnosis of SLE

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SLE - ANA

• ANA Major pathogenetic significance• Four types

1.Ab to DNA2.Ab to Histone3.Ab to non-histone proteins bound to RNA4.Ab to nucleolar Ag

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SLE - ANA

• Detected by Indirect Immunoflurorescence• Four basic staining pattern

1.Homogenous / diffuse nuclear stainingAb to chromatin & histone

2.Peripheral staining Ab to double stranded DNA

3.Speckled pattern – least specific4.Nucleolar pattern – Ab to nucleolar RNA

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Homogenous/ diffuse

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Peripheral

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Speckled

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Nucleolar

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SLE - ANA

• IIF test for ANA is positive in all SLE patients

• Highly sensitive / Not specific• Anti ds DNA & anti Sm Ag – Diagnostic of

SLE• Others – Anti histone, nuclear RNP, SS-A,

SS-B, scl-70

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SLE – other tests

LE cellPhagocytic leukocyte (neutrophil) that

engulfed the denatured nucleus of an injured cell

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Diagram of sequence of formation of LE cells in vitro

Phase-I Phase-II

Phase-III

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LE CELL

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LE prepLE prep

• Traumatize leucocytes by rotating 10ml of defibrinated blood with glass beads

• Incubating the prep for 1hour at 37°C• Separate the buffy coat and make a smear• Stain with leishman stain• Observe under oil immersion

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LE cells may also be seen inLE cells may also be seen in

• Pericardial effusions• Pleural effusions• CSF• Synovial fluid

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Morphological variants of LE cells

• LE body• LE rosette

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“Tart cellTart cell”• It’s a monocyte / histiocyte with engulfed viable

nuclear material• It’s not to be equated with LE cell• It has no diagnostic value• Importance: It should not be mistaken for LE cell

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Lupus band testAPR-2015-CSBRP

Rheumatoid ArthritisRheumatoid Arthritis

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Reitter’s syndromeReitter’s syndrome

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IRITIS

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PEMPHIGUS VULGARIS PEMPHIGUS VULGARIS

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Sjogren’s syndromeSjogren’s syndrome

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Polyarteritis NodosaPolyarteritis Nodosa

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Hashimoto thyroiditis

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Pernicious anemiaAbs against gastric parietal cells

causes atrophic gastritis, achlorhydria and reduced secretion of IF

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Goodpasture syndrome Goodpasture syndrome

Autoantibodies directed to components of the basal membranes of lung alveoli and kidney

glomeruli induce complement activation and a local inflammatory response which leads to

tissue damage

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How is Goodpasture's Syndrome Diagnosed?

When a patient presents with the initial indicators of Goodpasture's Syndrome (hemoptysis and hematuria), an anti-GBM antibody titer, bronchoscopy and renal biopsy may provide a definitive diagnosis of GS (Avella et al., 1999). 

The anti-GBM antibody titer is indicated when patients have acute renal failure, pulmonary hemorrhage and/or rising serum creatine concentrations with hematuria (Hellmark et al., 1997). 

The Anti-GBM antibody titer may eliminate other disorders, as these symptoms may be indicative of other diseases (Hellmark et al., 1997). 

A definitive diagnosis of GS will include an anti-GBM Ab titer test of greater than 20 units (normal = 0-9 units), bloody secretions in the bronchoscopy, and a linear distribution of IgG on the basement membrane of the renal biopsy (Avella et al., 1999). 

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Insulin dependent diabetes mellitus

50% may have islet cell Abs (ICAbs) at the time of diagnosis

ICAbs in family members indicates a high risk of subsequent diabetes

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AIHAAIHA

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SclerodermaScleroderma

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systemic sclerosis- hands showing tight shiny skin sclerodactyly, flexion contracture of fingers and thickening of tendon sheath.APR-2015-CSBRP

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Grave’s diseaseGrave’s disease

Abs to TSH receptors on thyroid acinar cells (TSA)TSA is stimulatoryTSA is absent in nodular goitre / adenoma

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Marty Feldman

(1934 – 1982) English writer, comedian Notable for his bulging eyesHe wrote situation comedies such as The Army Game He also appeared in ‘The Adventure of Sherlock Holmes’

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DeramtomyositisDeramtomyositis

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Multiple sclerosisMultiple sclerosis

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Myasthenia gravisMyasthenia gravis

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Vitiligo

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VitiligoAPR-2015-CSBRP

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E N D

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