Immunology Flashcards
What are the characteristic Ab involved with RA?
RF-Rheumatoid factor
ACPA-anti-citrullinated peptide antibody. Positive test early indicates more severe disease.
Self reactive Ab to citrulline residues which are the result of posttranslational modificaiton of Arg.
High citrullination is BAD
Why are the joints commonly affected in RA?
One reason is that the classic RF is an IgM antibody with reactivity to the Fc region of IgG and forms immunecomplexes that are deposited in the joints. This causes complement cascade activation and is a Type III hypersensitivity reaction and chronic inflammation (through recruitment of inflammatory cells by Th-17).
The formation of these type of immune complexes is also found in SLE and sjorens.
Another reason is that fibroblast produce cytokines and chemokines that recuit an inflammatory response which in turn activates the adaptive immune system.
What types of T-cells are active in RA and how are they activated? What’s the result of these sensitizes T-cells on the synovial tissue?
Th-1- stimulated by IL12
Th-17- stimulated by TFG-B (suppress T reg which could inhibit an immune response with IL-10)
What type of cytokines does Th-17 produce and what type of cells are recruited? What are the general effects of Th-17?
Th-17 produces IL-17 activates neutrophils
IL-22 induces anti-microbial activity
TNF-alpha inflammatory mediator
Which molecules preferentially bind citrullinated peptides? What are some risk factors for high citrullination?
HLA-DR4
Smoking, peridontal disease, inflammation.
List the proposed Ag in RA and explain how citrullination may alter the immunogenicity of these Ag.
Ag- IgG Filagren Vimentin Collagen Fibronectin G-6 phosphate isomerase Proteoglycan
citrilline by its association with these molecules can make them more immunogenic to an HLA-DR4 MHC II receptor.
What are some predisposing genetic factors for RA?
Association with MHC genes and mutations in genes involved in T cell activation and cytokine secretion
Also viral component- EBV, CMV
Estrogen contributes to a more robust immune system which may be why they also have higher risk of auto immune disease.
Age- with age comes mutation and increased risk of auto immunity.
What are some biological targets used in the treatment of RA?
neutralize pro-inflammatory cytokines-IL-1,IL-6, and TNF-alpha, B-cells with Mab to CD20, and CD80/86
IL-1 is bound to cells and soluble in serum, so if the area around the joint is flooded with IL-1 receptor it can neutralize the free floating cytokine.
Deplete cells from the inflammatory site, by blocking integrin binding which permits leukocyte extravasation as they move toward the inflammed joint.
Down modulate co-stimulatory molecules and induce peripheral anergy.
What are the various ways in which an inflammatory cytokine can be blocked?
Mab can bind soluble cytokine thereby competing with a receptor. Also, receptor agonists can be used or anti-inflammatory cytokines can suppress the immune response (not as effective).
What enzyme converts Arg to citrulline?
PADI4 – peptidyl arginine deiminase type IV. Post transcriptional modification. Also, part of Urea cycle, and myelin basic protein normally contains it which is bad news in the case of MS.
Which is presented on APC only? HLA-B27 or HLA-DR4? What autoimmune disease is associated with each one?
HLA-DR4 MHC II RA
HLA-B27 MHC-1 SpA
Where are the player in the adaptive response in RA located and why? How does this help with detection of the disease?
Both in the joint and in the Lymph node.
In the lymph node DC/APC can interact with T-cells which then stimulate the differentiation and proliferation of B-cells into plasma cells and memory cells, the former produces massive quantities of Ab which are detectable in serum tests.
What’s the big picture in RA in regard to its initiation and continuation?
Genetic risk factors in citrullination (PAD14) or HLA-DR4, gender
Environmental factors-smoking, viruses, ageing
Acute tissue damage stimulate synovial fibroblast to produce cytokines and chemokines
Innate immune system (complement activated)
Inflammation
Lymphocytes and macrophages attracted by inflammatory response in joint space
Self-antigens processed and presented
Citrullination exacerbates the problem by increasing the affinity of Ag bound to HLA-DR4 molecules
CD4+ Th1 and Th17 cells activated
Antibody produced; CD8+ T cells activated
Chronic inflammation
What is Juvenile idiopathic arthritis?
What is ankalosing spondylitis?
Like RA for kids under 16
Chronic Inflammatory disease affecting the spine “bamboo spine”. Associated with HLA-B27 MHC I 90%
