Autoimmunity
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AUTOIMMUNITY. Johan van Rensburg. What goes wrong?. Tissue damage due to antibodies T cells Etiology multi-factorial environmental genetic specific HLA genotypes. Self antigens. HLA II > HLA I. Tolerance. Tolerance to self-antigens deletion of self-reactive B and T cells

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Autoimmunity

AUTOIMMUNITY

Johan van Rensburg


What goes wrong

What goes wrong?

  • Tissue damage due to

    • antibodies

    • T cells

  • Etiology multi-factorial

    • environmental

    • genetic

      • specific HLA genotypes

Self antigens

HLA II > HLA I


Tolerance

Tolerance

  • Tolerance to self-antigens

    • deletion of self-reactive B and T cells

      • during maturation in the bone marrow and thymus

  • Recognition of peptide/MHC complexes by peripheral T cells

    • In the absence of costimulatory signals

No activation of potentially

self-reactive T cells

Anergy


Tolerance1

Tolerance

  • Regulatory(suppressor) T cells

  • Immunologically privileged sites

    • eye

    • brain

TGFBIL-10

IL-4

Clonal expansion of autoreactive cells

Do not normally encounter immunocompotent cells

Self antigen inaccessible or in to low quantities


Autoimmune disease

Autoimmune disease

  • Lack of tolerance

  • Triggered by

    • Infection

    • Other environmental factors

    • Unknown

Increased/ aberrant expression of costimulatory molecules

Changing antigenicity of infected tissue (now a target)

Molecularmimicracy(eg. Rheumatic fever)

Superantigens

Stimulates families of T cells expressing a particular TCR-Vß segment


Autoimmunity

GENETIC PREDISPOSITION

MHC-class II genes

Other MHCgenes

Multiple non-MHC genes

Environmental

factors

CD4+ T cell

driving force

(autoreactive)

Autoreactive B cells

CD8+ T-cells

IgG

autoantibodies

Non T cell

effector cells

Cell-mediated

organ damage

Autoantibody mediated

organ damage


Systemic connective tissue disease

SYSTEMIC CONNECTIVE TISSUE DISEASE


Systemic connective tissue disease1

Systemic connective tissue disease


Systemic lupus erythematosis sle

Systemic Lupus Erythematosis (SLE)


In general

In general

  • Most common of multisystem connective tissue disease

    • Geographical

    • Racial

      • Caucasians

        • 30/100 000

      • Afro-caribians

        • 200/100 000

    • Gender

      • 90% Women

    • Age

      • Peak

        • 2nd to 3rd decades


Etiology and pathogenesis

Etiology and pathogenesis

  • Polyclonal B and T cell activation

    • Circulating auto-antibodies

      • Multi-organ involvement

        • Wide variety of clinical presentation

      • ~50 autoantigens identified

        • Hidden from Immune system in health

          • Intranuclear

          • Intra-cellular

    • Possible mechanisms

      • Environmental factors

        • Apoptosis

          • Autoantigens expressed on cell surface

        • Induce flares of SLE

          • Pregnancy

          • Infection

          • Sunlight


Diagnosis

Diagnosis

  • Revised ACR criteria for SLE

    • 4/11 in present or past

      • 4 mucocutaneous

      • 4 Systems

      • 1 pleura/pericardial/peritoneum (PPP)

      • 2 Auto-antibody

    • Anti-dsDNA

      • 30-50% of patients

      • ANA negative unlikely for SLE

      • Unless (Ro) positive

        • Most have skin rashes


4 mucocutaneous

4 mucocutaneous

  • Malarrash

    • Erythema

      • Fixed

        • Flat

        • Raised

        • Sparing nasolabial folds

  • Discoid rash

    • Erythematous

      • Raised patches

      • Adherent

        • Keratotic scaring

        • Follicular plugging

  • Photosensitivity

    • Skin rash

      • Sun burn areas

  • Oral ulcers

    • May be painless


Malar rash

MALAR RASH


Subacute cutaneous lupus

SUBACUTE CUTANEOUS LUPUS


Discoid lupus lesions

DISCOID LUPUS LESIONS


Alopecia

ALOPECIA


Alopecia1

ALOPECIA


Mouth ulcers

MOUTH ULCERS


Mouth ulcers1

MOUTH ULCERS


Early vasculitic lesions

EARLY VASCULITIC LESIONS


4 systems

4 Systems

  • Arthritis/arthralgia

    • Non-erosive

    • 2 or more peripheral joints

    • (Jaccoudarthropathy)

  • Renal

    • Proteinuria

      • Persistent

        • >0.5g/day

    • Cellular casts

      • Red cell

      • Granular

      • Tubular

  • Neurological

    • Seizures

    • Psychosis

    • Absence

      • Offending drugs

      • Metabolic derangement

  • Hematological

    • In absence of offending drugs

      • Hemolytic anemia

      • Leucopenia

        • <4000/mm3

          • 2 separate occasions

      • Lymphopenia

        • <1500/mm3

          • 2 separate occasions

      • Thrombocytopenia

        • <100 000/mm3

          • 2 Separate occasions


Jaccoud arthritis

JACCOUD ARTHRITIS

Jaccoud Sigismond, French physician, 1830–1913


Glomerulonephritis

GLOMERULONEPHRITIS

  • Minimal change

  • Mesangeal

  • Focal proliferative

  • Diffuse proliferative

  • Membranous glomerulonephritis

  • End Stage renal failure

    • (Typical is that the complement is diminished)


Mesangial lesions

MESANGIAL LESIONS


Focal proliferative gn who class iii

FOCAL PROLIFERATIVE GN (WHO CLASS III)


1 pleura pericardial peritoneum ppp

1 pleura/pericardial/peritoneum (PPP)

  • Serositis

    • Pleuritis

      • Pleuritic pain

      • Rub

      • Effusion

    • Pericarditis

      • ECG

      • Rub

      • Effusion


2 auto antibody

2 Auto-antibody

  • Immunology

    • Anti-DNA antibodies

    • Anti-SM antibodies

    • Antiphosfolipid antibodies

  • Antinuclear antibodies (ANA)

    • Abnormal titer

      • By immunofluorescence


Clinical features more than criteria

Clinical features(more than criteria)

  • Raynaud's phenomenon

  • Musculoskeletal

  • Mucocutaneous

  • Renal

    • Management

  • Cardiopulmonary

  • Central nervous system

  • Hematological

  • Other


Lipmann sacks endocarditis

Lipmann Sacks Endocarditis


Gangrene of the toe

GANGRENE OF THE TOE


Osteonecrosis

OSTEONECROSIS


Polymyositis and dermatomyositis

Polymyositis and Dermatomyositis


Classiffication

Classiffication

  • Adult polymiositis

  • Adult dermatomyositis

    • Important

      • Malignancy

  • Childhood dermatomyositis


Clinical picture

Clinical picture

  • Proximal muscle weakness

  • Skin manifestations

    • NOT typically sun exposed areas

      • Malar rash

      • Heliotropic rash

      • V-sign

      • Shawel sign

      • Gottron’s nodules

      • Mechanic hands


Malar and heliotropic rash

MALAR AND HELIOTROPIC RASH

Upper eyelid

Involving nasolabial folds


V sign

V-sign


Gottron s nodules

Gottron’s Nodules


Differential diagnosis nb

Differential diagnosis (NB)

  • Inclusion body myositis

  • Other causes of proximal muscle weakness

    • See Davidson’s


Sjogren s disease

Sjogren's disease


Clinical features

Clinical features

  • Risk markers

  • Common clinical features

  • Less common features

  • Auto antibodies

  • Associated autoimmune disorders


Scleroderma

Scleroderma


Scleroderma systemic sclerosis

Scleroderma (systemic sclerosis)

Scleros: hard

Derma: skin


Systemic sclerosis

SYSTEMIC SCLEROSIS

Multisystem disorder

Fibrosis of the skin, bloodvessels, and viseral organs

Affected organs: Lungs

Heart

Kidneys

GIT


Classification

CLASSIFICATION

  • Limitedcutaneous disease

  • Diffusecutaneous disease

  • Sinescleroderma

  • Undifferentiated connective tissue disease

  • Overlapsyndromes


Limited cutaneous scleroderma

Limited cutaneous scleroderma

  • Skin thickening: Distal to elbow and knee

    Face and neck

  • Synonym: CREST Syndrome


Diffuse cutaneous scleroderma

Diffuse cutaneous scleroderma

  • Skin thickening includes: Trunk

    Face

    Proximal extremities

    Distal extremities


Sine scleroderma

Sine scleroderma

  • Internal organ manifestations

  • Vascular abnormalities

  • Serologic abnormalities

  • Noclinical detectable skin change


Undifferentiated connective tissue disease

Undifferentiated connective tissue disease

  • Raynaud’sphenomenon

  • Clinical and/or serologic features of systemic sclerosis (digital ulceration, abnormal nail fold capillary loops, s-anticentromere antibody, finger edema)


Overlap syndrome

Overlap syndrome

  • Systemic sclerosis in association with other connective tissue disorders

  • Eg; SLE

    Inflamatory muscle disease

    RA


Incidence

INCIDENCE

  • 4-12/million/year (may be more than fourfold higher)

  • All geographic areas

  • All racial groups

  • All ages (Peak onset between 30 and 50)

  • M:F - 4:1 (Childbearing age at peak risk)

  • Sporadically (weak links to exposure to environmental toxins eg. silica and silicone)


Familial ssc

Familial SSc

  • Other connective tissue diseases and autoantibodies in relatives - ?hereditary

  • Increased ANA in spouses - ?environmental

  • Relationship between HLA types and specific autoantibodies:

    Anticentromere antibodies: HLA-DR1, -DR4, -DR5,

    -DQB1

    Antitopoisomerase antibodies: HLA-DR5,-DQB1


Pathogenesis

PATHOGENESIS

  • Immunologic mechanisms

  • Vascular damage

  • Activation of fibroblasts

  • Overproduction and accumulation of collagen and other extracellular matrix proteins in skin and other organs


Clinical manifestations

Raynaud’s phenomenon

Skin thickening

Subcutaneous calcinosis

Telangiectasia

Arthralgias / arthritis

Myopathy

Esophageal dysmotility

Pulmonary fibrosis

Isolated pulmonary arterial hypertention

Congestive heart failure

Renal crisis

CLINICAL MANIFESTATIONS


Raynaud s phenomenon

Raynaud’s phenomenon

  • Episodic vasoconstriction of small arteries and arterioles of fingers, toes, and tip of nose (brought on by cold, vibration, or emotional stress)

  • May precede skin changes by months / years (tipically within a year)

  • Frequently the first symptoms of SSc

  • 95% of SSc patients

  • History of digit pallor (most reliable symptom)

  • After two or more years: few develop SSc


Skin features

Skin Features

  • Early disease: Swollen fingers and hands,

    relatively spared lower

    extremities

  • Indurative phase: Skin becomes firm and

    thickend - eventually tightly

    bound to underlying

    subcutanious tissue


Skin features1

Skin Features

  • From distal to proximal

  • Rapid progression over 2- to 3-years: associated with greater risk for visceral dissease

  • Diffuse cutaneous scleroderma: Changes usually peak in 3 to 5 years and then slowly improves

  • Limited cutaneous Scleroderma: More gradual progression and may continue to worsen

  • Complications: Flexion contractures

    Ulcers and secondary infection

    Resorption of terminal phalanges

    Dark pigmentation of skin

    (also hypo- pigmentation)

    Dry and coarse


Skin features2

Skin Features

  • Subcutaneous calcinosis:

    Periarticular, digital pads, olecranon and prepatellarbursae, along extensor areas of forearms

  • Face:

    Loss of wrinkles and facial expresion

    Microstomia and perpendicular wrinkles to lips

    Pinched or beadlike nose


Telangiectasia

Telangiectasia

  • On fingers, face, lips, tongue, and buccal mucosa

  • After several years

  • Limited scleroderma (85%)

  • Diffuse scleroderma (40%)

  • Capillary beds of nail folds:

    Limited form: enlargement of capillaries

    with little or no capillary loss

    Diffuse form:disorganization of capillary beds with

    dilated capillaries interspersed with areas where

    capillaries have disapeared


Musculoskeletal features

Musculoskeletal Features

  • Symmetric polyarthritis(like RA)

  • Leathery crepitation over moving joints

  • Carpal tunnel syndrome

  • Muscle weakness(disuse and atrophy)

  • Myopathy(Normal muscle enzymes)

  • Myositis(proximal weakness and raised muscle enzymes)

  • Bone resorption(terminal phalanges, ribs, clavicle, angle of mandible)


Git features

GIT Features

  • Dysphagia

  • GERD and peptic esophagitis

  • Barrett’s metaplasia

  • Delayed gastric emptying

  • Pseudo-obstruction of small intestine

  • Malabsorption syndrome

  • Pneumatosis intestinalis

  • Benign pneumoperitonium

  • Chronic constipation and fecal impaction

  • Intussuception

  • Diverticulae

  • Incontinance and anal prolapse

  • GIT- bleeding (because of telangiectasia)


Pulmonary features

Pulmonary Features

  • Exertional dyspnea

  • Dry non-productive cough

  • Restrictive lung disease:

    Pulmonary fibrosis (40%)

    Restriction of skin movement

  • Aspiration pneumonia

  • Alveolar cell and bronchogenic carcinoma

  • Pulmonary arterial hypertension (mean survival then plus-minus 2 years)


Cardiac features

Cardiac Features

  • Pericarditis

  • Heart failure

  • Heart block and arrhythmias

  • Angina pectoris (some have normal angiograms)

  • Cor-pulmonale


Renal features

Renal Features

  • Mostly those with diffuse cutaneous scleroderma

  • Renal crisis:

    • Malignant hypertension, wich can rapidly progress to renal failure

    • Presents with encephalopathy, severe headache, retinopathy, seisures, and left ventricular failure

    • Hematuria and proteinuria followed by oliguria and renal failure

  • Indicator of impending renal failure

    • Microangiopathic anemia

    • Chronic pericardial effusion


Other features

Other Features

  • Sicca-syndrome

    • Sjogren’s

    • Intra- and periglandular fibrosis

  • Hypothyroidism

    • Antithyroid antibodies

    • Fibrosis of the thyroid

  • Trigeminal neuralgia

  • Male impotence

  • Biliary cirrhosis


  • Laboratory findings

    Laboratory Findings

    • Raised ESR

    • Hypoproliferative anemia

    • Iron deficiancy anemia

    • Macrocytic anemia (B12 and folic acid deficiancy)

    • Microangiopathic hemolytic anemia

    • Hypergammaglobulinemia (mostly IgG)

    • RF positive in 25%

    • ANA positive in 95% (Hep-2)


    Autoantibodies in ssc

    Autoantibodies in SSc

    • Antitopoisomerase 1 (Scl-70)

      • 40% in diff. cut. ssc.

  • Anticentromere

    • 60-80% in lim. cut. Ssc.


  • Diagnosis1

    Diagnosis

    • Raynuad’s with tipical skin lesions and visceral involvement

    • Linear scleroderma and morphea

    • Sine scleroderma

      • Unexplained

        • Pulmonary fibrosis

        • Pulmonary hypertension

        • Cardiomyopathies

        • Heart block

        • Dysphasia

        • Malabsorption


    Other causes of raynaud s

    Other causes of Raynaud’s

    • Thoracic outlet syndromes

    • Shoulder-hand syndrome

    • Trauma

    • Previous cold injury

    • Vinyl chloride exposure

    • Circulating cryoglobulins or cold agglutinins


    Chemically induced scleroderma like disorders

    Chemically induced scleroderma-like disorders

    • Toxic-oil syndrome

    • Vinyl chloride-induced disease

    • Bleomycin-induced fibrosis

    • Pentazocine-induced fibrosis

    • Epoxy- and aromatic hydrocarbons-induced fibrosis

    • Eosinophilia-myalgia syndrome


    Other scleroderma like disorders

    Other scleroderma-like disorders

    • Sclerema adultorum of Buschke

    • Scleromyxedema

    • Scleredema

    • Chronic graft-vs.-host disease

    • Eosinophilic fasciitis

    • Digital sclerosis in diabetes

    • Primary amyloidosis and amyloidosis associated with multiple myeloma


    Prognosis

    PROGNOSIS

    • Limited cutaneous scleroderma (anti centromere antibodies)- Good prognosis with exception of pulmonary arterial hypertension (< 10%)

    • Diffuse cutaneous disease - Worse prognosis - Viceral organ disease develop early

    • Males - Worse prognosis

    • Overall 5 year survival: 86%

    • Overall 10 year survival: 69%

      (HESSELSTRAND, ET AL: MORTALITY AND CAUSES OF DEATH IN A SWEDISH SERIES OF SYSTEMIC SCLEROSIS PATIENTS. ANN RHEUM DIS 1998;57:682-686)


    Causes of death

    CAUSES OF DEATH

    • Pulmonary complications (Most frequent)- Fibrosis- Pulmonary Hipertension- Pneumonia- Pulmonary Malignancy (Mostly adenocarcinomas)

    • Cardiovascular

    • Renal crisis (< frequent since ACE-inhibitors)

      HESSELSTRAND, ET AL: MORTALITY AND CAUSES OF DEATH IN A SWEDISH SERIES OF SYSTEMIC SCLEROSIS PATIENTS. ANN RHEUM DIS 1998;57:682-686)

      (


    Treatment

    Treatment

    • Cannot be cured

    • Treatment of involved organ systems

      • Relieve symptoms

      • Improves function

    • Doctor-patient relationship is important

      • Explanations and reassurances

    • Monitor

      • Blood counts

      • Urinalysis

      • Renal function

      • Pulmonary function


    Immunosuppressives

    Immunosuppressives

    • Entelin-1 receptor antagonists

    • Azathioprine

      • With life-treatening disease

      • Studies are lacking


    Antiplatelet therapy

    Antiplatelet Therapy

    • Aspirin

      • Block the formation of Thromboxane A2

    • Dipyridamole

      • Decreases platelet adhesion

        A two year double blind study did not show any benefit


    Glucocorticoids

    Glucocorticoids

    • Inflammatory myositis

    • Pericaditis

    • May decrease edema of edematous phase

    • Not for long term treatment of SSc

    • High dosis may precipitate renal failure


    Management of raynaud s

    Management of Raynaud’s

    • General

      • Dress warmly

      • NO SMOKING

      • Remove causes of external stress

      • Avoid drugs like amphetamine and ergotamine

      • NO beta-blockers

  • Blockers of sympathetic vasoconstriction

    • Reserpine, methyldopa, phenoxibenzamine, prazocin

  • Calcium channel blockers

    • Adalat XL

  • Other

    • Ketanserine (serotonin antagonist)

    • Iloprost

    • Pentoxifylline


  • Renal crisis

    RENAL CRISIS

    • ACE-Inhibitors

    • Dialysis

    • Treat hypertension

      • Beware of beta-blockers


    Autoimmunity

    END


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