Immunology of RA & SLE Flashcards
What is SLE& what type of hypersensitivity reactivity reaction is it
- Systemic Lupus Erythematosus
- Skin rash caused by complexes of DNA & anti-DNA abs becoming localized in the skin to cause inflammation
- Type III hypersensitivity reaction
Outline the epidemiology of Lupus
- Most common in African-Americans ( 1 in 1000)
- Gender bias 10:1 female to male
- Age of onset: peaks in the 3rd/4th decade ( female)
What are the clinical features of SLE?
- Any organ/tissue
- Common patterns
- Immune complex deposition in the synovial membranes in the joints
- Skin( diverse patterns, photosensitivity, alopecia)
- Joints (non-erosive arthritis and tendinitis)
- Sicca symptoms ( salivary, lacrimal, genital tract)
- Glomerulonephritis ( several patterns: mesangial, membranous & peripheral)
- Neurological: CNS, eye, PNS
What pathologies can SLE bring to the eye?
- Blindness
- Retinal exudates
- Conjunctivitis
- Sjogrens syndrome
What pathologies can SLE bring to the skin covering?
- Baldness
- Discoid LE
- Butterfly rash
- Raynauds syndrome
- Photosensitivity
- Mucosal ulcers of the nose, mouth & vagina
What pathologies can SLE bring to the kidney?
- proteinuria
- kidney failure
- odedema
- Hypertension
What pathologies can SLE bring to the GI tract?
- Poor appetite
- Vomiting
- Diarrhoea
What pathologies can SLE bring to the musculoskeletal system?
- Arthralgias
- Arthritis
- Mastalgias
What pathologies can SLE bring to the Reproductive system?
- Menorrhagia
- Amenorrhoea
- Prematurity
- Still births
What pathologies can SLE bring to the Lining membranes?
- Pericarditis
- Pleurisy
- Endocarditis
Define menorrhagia
abnormally heavy bleeding at menstruation
Explain lymphadenopathy in SLE
- Can cause liver & spleen enlargement
What is pleurisy and what is its most common symptom
-Inflammation of the pleura ( the sheet-like layers that cover the lungs)
Most common symptom= sharp chest pain when breathing deeply
What pathologies can SLE bring to the blood?
- Decreased platelets
- Abnormal autoantibodies
What pathologies can SLE bring to the CNS?
- seizures
- paralysis
- neuropathies
- psychiatric disorders
- Headaches or migraines
Outline the clinical immunology of SLE
Abnormal apoptosis exposes nuclear antigens…
- antinuclear autoantibodies (ANA): multiple components
- Anti-dsDNA
- Anti-histone
- Antibodies to extractable nuclear antigens( ENA): anti-Ro/ Anti-La ( RNA processing) ; anti-RNP/ anti-SM( spliceosome)
- Rheumatic factor
- Anti-cardiolipin antibodies
Function of a spliceosome?
Removes introns from a transcribed pre-mRNA, a type of primary transcript
Cardiolipin function?
Found almost exclusively in the inner mitochondrial membrane where it is essential for the optimal function of numerous enzymes that are involved in mitochondrial energy metabolism.
Outline the mechanisms of antibody injury in SLE
- Direct cytotoxicity (& clearance) e.g autoimmune haemolytic anaemia, thrombocytopenia
- Immune complex formation& deposition eg skin rashes, glomerulonephritis
- Trigger pro-inflammatory responses in cells carrying Fc gamma receptors
- Promote NK cell activation and/or cytotoxicity
How does the immune system present in SLE?
- Complement consumption ( by immune complexes)
- Excess production of alpha-IFN ( many cells): a state of ‘pseudo-viral infection’ by immune complexes
- Activation of Toll-like receptors (TLR7/9 bind DNA & RNA)
- Activation of neutrophils
What type of hypersensitivity reactions is RA
Type II, III & IV
How can we use the start of the disease to distinguish between RA & OA?
OA starts in the weight bearing joints
RA starts in the peripheral joints ( toes/fingers) then makes its way up
What are the differences between normal and arthritic joints?
Arthritic joints have:
- Bone ends that rub together
- Swollen inflamed synovial membrane
- Bone erosion
- Thinned cartilage
What’s the female:male ratio of RA?
3:1
What is RA?
Rheumatoid arthritis is…
- Systemic autoimmune disease of unknown aetiology
- Manifests mainly in joints
- Extra-articular involvement
- Chronic inflammatory disease
Explain the pathogenesis of RA
- Pannus (Inflammatory tissue) eats away the underlying bone
- Extensive angiogenesis= a marker of chronic inflammation
- Hyperplastic synovial lining :the single layer of synovial cells have proliferated; now multiple layers
Why is RA not considered a type I hypersensitivity reaction
-The mast cells aren’t being activated by binding IgE & cross-linked by allergens
Outline the evidence for cellular involvement in RA
Synovial membrane:
- Synovectomy relieves symptoms for several years
- Macrophages: Type A synoviocyte (Non-fixed cells that can phagocytose actively cell debris and wastes in the joint cavity, and possess an antigen-presenting ability.)
- Fibroblasts: Type B synoviocyte (FLS)
MMP-1,-3 & -9
Cytokines, TNF, IL-1. IL-6
Chemokines, CCL2,CCL5, IL-8
Explain the predisposition to RA
Genetic:
- HLA-DR 1/ HLA-DR4
- Common epitope QKRAA(Not associated with all ethnic groups)
- Single nucleotide polymorphisms (SNPs eg PTPN22)
- Heretability of MZ twins 15%
What is deimination?
- aka citrullination
- The conversion of the amino acid arginine in a protein into the amino acid citrulline
- The immune system can attack citrullinated proteins, leading to autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS)- due to anticitrullinated protein antibodies
Explain the significance of anti-citullinated antibody cyclic citrullinayted peptide (CCP) in RA
- Citrulline caused by deimination of arginine residues
- Great specificity for RA
- Expression of anti-CCP correlates with the carriage of certain genes on the HLA-DRB1 locus
- Highly significant association between anti-CCP and HLA-DR4, and a weaker but still significant association with HLA-DR1
- May predict erosive disease
Describe the evidence for the involvement of T cells in the pathogenesis of RA
- ) Association with HLA-DR4/DR1
- ) RA & HIV-1 infection
- ) Activation of RA by IL-2 infusion
- ) Anti T cell therapies
- ) Synovial histology
- ) Synovial T cells: activation/cytokines
What is the main function of IL-2
To promote the development of Treg cells
Explain the evidence for the association of RA with HLA-DR
- CD4 cells are MHC class II restricted
- HLA-DR4 positivity associated with more severe disease
- HLA-DR1 & HLA-DR4 shared epitope hypothesis QKRAA motif
Describe rheumatoid synvoial membrane
- Thickening of the synovial lining layer: Proliferation of fibroblast-like synoviocytes
- Angiogenesis
- Influx of mononuclear cells ( T& B cells and monocytes)
- Production of cytokines, chemokines & matrix metalloproteinases
What is the main autoantibody associated with RA?
- Rheumatoid factor (non specific & non pathogenic)
- Diagnosis
- 80% RA patients are RF+
- Present in sera many months before disease is apparent
What can happen to the bone in RA
- Bone erosions
- Osteoclast activations
Why are T cells pro-inflammatory
- Direct cell contact between activated T cells and monocytes induces IL-1Beta production
- Direct cell contact between T cells and FLS( fibroblast like synoviocytes) induces MMP production
- Direct cell contact between T cells and FLS induces MCP-1 production
