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
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.
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.
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
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
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.
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
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.
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 .
» 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
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