Autoimmune disease III

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AUTOIMMUNITY- III

Autoimmunity Part-III

 At the end of the session the student should be able to:

 a. Describe the pathogenesis of important autoimmune disorders:

 1) SLE.

 2) Rheumatoid arthritis.

 3) Sjogren ’s syndrome etc.

Suggested readings: Robbins basic pathology, 8th edition.

Page:139 - 152

Diagnostic criteria for autoimmune diseases

Three requirements should be met:

 (1) Presence of an immune reaction specific for some self-antigen or self-tissue .

 (2) Evidence that such a reaction is not secondary to tissue damage but is of primary pathogenic significance .

 3) Absence of another well-defined cause of the disease.

How to establish the Diagnosis

 History: characteristic symptoms

 Classical physical findings and signs

 Imaging& Laboratory studies:

» Radiological

» General: UG, CBC, ↑ESR, ↑CRP, RF

» Hormonal assay

» ? HLA

» Renal and skin biopsy – H&E + IF

» Auto-antibodies Screening (serology, IF)

SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

 SLEa multisystem disease of autoimmune origin, characterized by a vast array of autoantibodies , particularly antinuclear antibodies ( ANAs ).

 SLE predominantly affects women.

 SLE manifest in any age even early childhood

 Clinical presentation:

 complex of criteria approved by (American society of rheumatology), different presentation.

Acute or insidious in its onset, chronic, remitting and relapsing .

 febrile illness , injury to the skin, joints, kidney, and serosal membranes. other organ in the body,

SLE- Pathogenesis

 The cause of SLE remains unknown.

 SLE —both documented and postulated—are as varied and complex

 The pathogenesis :

 1) Genetic factors.

 2) Immunological factors

 3) Environmental factors .

 Outcoms

 Antibodies against self-constituents ( SM,

Nuclei, Nucleoli, DNA) due to a failure of the mechanisms that maintain self-tolerance.

1)

SLE- Pathogenesis

Genetic susceptibility. contributions from

MHC and multiple non-MHC genes

 Evidence support a genetic predisposition:

 a) Family historyincreased risk .1

st degree.

 b) Monozygot twins – higher rate

 c) Studies of HLA associationsHLA-DQ locus > produce Anti-sm, DNA, Phospholipid.

 d) Inherited deficiencies of early complement components, such as C2, C4, or C1q.>> impair removal of circulating immune complexes& Tissue deposition + loss of B tolerance.

SLE- Pathogenesis

 2) Immunological Factors: a) b)

Defective elimination of self-reactive B cells

Escape tolerance CD4+ helper T cells specific for nucleosomal antigens>production autoantibodies .

c)

Nuclear DNA and RNA contained in immune complexes may activate B lymphocytes.

d)

The role of cytokines ( interferons-1, TNF ), release as response to Viral infection lead to >> activate dendritic cells, B cells& promote T

H

1 responses> production of autoantibodies .

SLE- Pathogenesis

 3) Environmental Factors: a)

Exposure to ultraviolet (UV) light exacerbates SLE>> induce enhance inflammation , apoptosis & alter the DNA

>> Immunogenic.

a)

Sex hormones > exert an important influence on the occurrence and manifestations of SLE. b)

Drugs such as hydralazine , procainamide , and D penicillamin > induce an SLE-like response.

Rheumatoid arthritis

 RA- defined as autoimmune disease (multisystemic, non-organ specific) with Articular &

Extra-articular manifestations.

 Articular lesionchr. by Non-suppurative proliferative synovitis, which leads to destruction of articular cartilage >> Lead to progressive disabling arthritis.

 Extra-articular manifestation may strongly resemble SLE or scleroderma- such as the skin, blood vessels, lungs, and heart.

 Age : Usual onset in decades 4 and 5

 Sex : 3-5X more common in women than in men

Rheumatoid arthritis

 Etio-Pathogenesis:

 precise trigger which initiates destructive immune response is not known

 Specificity of Pathogenic T Cells: Unknown antigen in joint synovium (type II collagen?); role of antibodies ?

 1Genetic susceptibility

 2- Environmental arthritogen

 3- Immunological factor

Rheumatoid arthritis-Pathogenesis

 1Genetic susceptibility :

 Non-HLA gene (PTPN22) > Tyrosine activity>> regulate and control T cell responses.

 HLA-DRB1 associated with increased incidence of the inflammatory synovitis.

 2- Environmental arthritogen (implicated not proven)

Smoking& infection(EBV,Proteus, M.tuberculosis).

 3- Immunological factors:

 3- 80% of +VE To RA factors (antibodies against

Fc portion of IgG ).

 Initiated by activation of T-helper cells which produce cytokines and activate B cells to produce antibodies.

Rheumatoid arthritis

 Clinical course

» symmetrical , polyarticular arthritis

» weakness, fever, malaise may accompany joint symptoms

» stiffness of joints in AM early, then progresses to claw-like deformities

» severely crippling in 15-20 years, life expectancy reduced 4-10 years.

» Amyloidosis develops in 5%-10% of patients

» Anemia of chronic disease present in late cases

Destructive

Rheumatoid Synovitis

 NORMAL Bi-Layered

Synovium

Sjogren’s syndrome- SS

 is a chronic Autoimmune disease chr. by

Dry eyes ( keratoconjunctivitis sicca ) and

Dry mouth ( xerostomia ) due to immune destruction of the lacrimal and salivary glands

 Sicca syndrome - this phenomenon occurring as an isolated primary syndrome.

 Extraglandular manifestations , such as cutaneous vasculitis,nephritis, etc …

 Frequently associated with RA , some with

SLE or other autoimmune processes.

Sjogren’s syndrome- SS

 Etio-pathogenesis of SS remains obscure

 1- Genetic- HLA gene : SS - associated with certain HLA alleles, HLA-DR3, HLA-B8,etc …

 2- Environmental factors : Viral infection of salivary glands “unclear relation”- e.g EPV HCV>> cells injury, death >> release self antigens>> B& T cell self activation .

 The Primary target is ductal epithelial cells of exocrine glands, by chronic inflammatory infiltrates :CD4-T& B cells-plasma cells .

Sjogren’s syndrome-SS

» Types of auto-antibodies :

» 75% of patient present with rheumatoid factor (an antibody reactive with self-IgG).

» 50- 80% Presented with ANA.

» 90% most have Ab against two ribonucleoprotein antigens anti -SS-A (R0) (early) and anti-SS-B (La) antibodies.

The outcome: Salivary gland destruction , inflammation , fibrosis >>dry eyes + dry mouth

Sjogren’s syndrome

 Clinical course

» primarily in women > 50-60

» dry mouth, Nose-difficult swallowing solid diet, cracks, fissures , Lack of tears-Blurring vision, thick secretion

» Salivary glands enlarged-50% parotid

» EXTRANODAL manifestation: recurrent bronchitis, and pneumonitis, lung fibrosis, RA-synovitis

» 1% develop lymphoma, 10% with pseudolymphomas

» The combination of lacrimal & salivary gland inflammatory event called Mikulicz disease/ syndrome

Thanks

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