Immunology of RA & SLE Flashcards by Ayoyinka Ololade

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

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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)

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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

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What pathologies can SLE bring to the eye?

Blindness
Retinal exudates
Conjunctivitis
Sjogrens syndrome

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What pathologies can SLE bring to the skin covering?

Baldness
Discoid LE
Butterfly rash
Raynauds syndrome
Photosensitivity
Mucosal ulcers of the nose, mouth & vagina

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What pathologies can SLE bring to the kidney?

proteinuria
kidney failure
odedema
Hypertension

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What pathologies can SLE bring to the GI tract?

Poor appetite
Vomiting
Diarrhoea

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What pathologies can SLE bring to the musculoskeletal system?

Arthralgias
Arthritis
Mastalgias

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What pathologies can SLE bring to the Reproductive system?

Menorrhagia
Amenorrhoea
Prematurity
Still births

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What pathologies can SLE bring to the Lining membranes?

Pericarditis
Pleurisy
Endocarditis

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Define menorrhagia

abnormally heavy bleeding at menstruation

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Explain lymphadenopathy in SLE

Can cause liver & spleen enlargement

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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

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What pathologies can SLE bring to the blood?

Decreased platelets

- Abnormal autoantibodies

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What pathologies can SLE bring to the CNS?

seizures
paralysis
neuropathies
psychiatric disorders
Headaches or migraines

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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

1. ) Association with HLA-DR4/DR1 2. ) RA & HIV-1 infection 3. ) Activation of RA by IL-2 infusion 4. ) Anti T cell therapies 5. ) Synovial histology 6. ) 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