PP of Autoimmune Diseases Flashcards
1
Q
72yo male presents to clinic w/ HA for 1 wk, progressively gotten worse - L side, 7/10, tyelonol doesn’t help, L temporal region swelling and tenderness w/ palpation, fever -
What dx test should you get? Dx? Tx?
A
- ESR
- Temporal Arteritis
- tx: tx now w/ prednisone at 40-60/day and schedule temporal artery bx in next few days
- visual changes are a red flag (need IV abx ASAP)
2
Q
What are the mechanisms hypothesized to be involved in breakdown of tolerance?
A
- failure to delete autoreactive lymphocytes:
central tolerance failure, peripheral tolerance failrure - molecular mimicry
- abnormal presentation of self ags
- epitope spreading (part of ag that is recognized by abs)
- polyclonal lymphocyte activation
3
Q
Source of T cells? Fxn?
A
- derived from thymus
- impt in cellular immunity
- induce B cells to produce abs
- each programmed to recognize unique processed peptide fragment by T cell receptor (TCR)
- circulate in blood, sequestered in spleen and lymph nodes
4
Q
Mechanism of T cell activation?
A
- dendritic cells and macrophages - ag presenting cells (APC)
- major histocompatibility (MHC) - a region formed by genetic loci that play a central role in humoral and cellular immunity
- MHC: HLA group of proteins that participate in APC
- When not self peptide APCs interact and present ag to T cells - CD4 and CD8. Normal ratio CD4/CD8 - 2:1
- CD4 T helper cells, CD8 cytotoxic T cells
5
Q
T cell response? Diff classes of MHC molecules?
A
- CD4 and CD8 expressing T cells are referred to as CD4 adn CD8
- the helper T cells - secrete cytokines and influence all other cells of the immune system
- Class I MHC molecules: assoc w/ recognition of endogenous ags
- Class II: assoc w/ recognition of exogenous ags
- Class III: involved w/ complement system
6
Q
Origin of B lymphocytes?
A
- derived from bone marrow
- 10-20% circulate
- present in: bone marrow, lymph nodes, spleen, tonsils and nonlymphoid organs such as GI tract (peyers patchs)
- after stimulation B cells form plasma cells and secrete immunoglobulins
7
Q
AG processing?
A
- Ag must be taken up by APC
- Ag is then processed inside the cell
- Then it is presented to immune system
- MHC class I/CD8: cytotoxic cell
- MHC class II/CD4 - helper T cells
8
Q
What is immunological tolerance?
A
- state of unresponsiveness specific for a particular Ag
- it prevents the body from attacking itself - self tolerance
9
Q
What is B cell tolerance?
A
- loss of self tolerance w/ development of autoabs is characteristic of number of autoimmune disease: hyperthyroidism in graves is due to autoabs to TSH receptors
filtering autoreactive B cells out of pop:
- clonal deletion in bone marrow
- deletion of autoreactive cells in spleen or lymph nodes
- functional inactivation by anergy
- receptor editing process that changes specificity of a B cell receptor when autoag is encountered
10
Q
What is central mechanisms of T cell tolerance?
A
involve the deletion of self-reactive T cells in the thymus - -immature T cells of a clone that are not auto-reactive T cells are allowed to mature = positive selection -immature T cell clones that have high affinity for host cells are sorted out and undergo apoptosis = negative selection - many autoags are not present in thymus which results in self reactive cells escaping the process: sequestered ags (immunologically priviledged) - CNS, eyes, testes (if these are released then immune response ensues) - therefore there needs to be peripheral mechanism available to deal w/ these
11
Q
Peripheral mechanisms of T cell tolerance?
A
- sometimes no problem exists b/t the self reactive T cells remain immunologically ignorant b/c they cant see Ag (BBB)
- peripheral activation of T cells requires 2 signals -
recognition of peptide Ag w/ MHCs on the APCs
and
secondary costimulatory signals which are often absent - Apoptosis (Fas receptor and Fas ligand)
- Suppressor T cells can also down-regulate autoreactive T cells
12
Q
Mechanisms of self tolerance?
A
- central tolerance: elimination of self-reactive T cells and B cells in central lymphoid organs
- peripheral tolerance:
some of the T cells will become regulatory T cells - products of Tr are cytokines that downregulate the immune response when the pathogen is cleared and help prevent autoimmunity - some escaped T cells won’t recognize MHC self ag and will remain as immature Tc cells
anergy: state of immunologic tolerance to Ag
13
Q
RFs of autoimmunity?
A
much remains unknown but possibilities have been proposed: (5-7% of pop is affected by autoimmunity):
- failure of mechanisms that maintain self tolerance
- genetic factors: genes that are involved in the immune response are the major players (MHC and HLA loci)
- gender: autoimmune diseases affects females more severely and more often than men - hormonal influences play a role (estrogen) - except Ankylosing spondylitis, and acute anterior uveitis
14
Q
Etiology of autoimmune disorders?
A
result from 1 or more mechanisms producing loss of self-tolerance:
- immunologic cells are involved in tissue injury that results in exposure of self-antigen
- precise mechanisms involved in initiating response is largely unknown
- more than one defect may be present in each disease and each mechanism may be involved in more than one disease
15
Q
Possible mechanisms of autoimmune mechanisms:
Failure of T cell mediated suppression?
A
- failure to delete autoreactive immune cells
- increasing ratio of CD4 to CD8 may be involved
16
Q
Possible mechanisms of autoimmune mechanisms:
release of sequestered Ags?
A
- normally body doesn’t produce Ab against self Ag
- any self Ag sequestered from immune system during development and then reintroduced is considered foreign
- ex: sperm and ocular Ag following post traumatic uveitis and orchitis following vasectomy
17
Q
Possible mechanisms: molecular mimicry?
A
- foreign Ag so closely resembles a self Ag that Ab produced against the foreigns Ag attack self Ags
- B cell or T cell response can be mounted against antigentically altered or injured tissue creating an immune response
- ex:
Rheumatic Fever and Acute Glomerulonephritis: a protein in the cell wall of group A Beta hemolytic strep has considerable similarity to Ag in heart and kidney
18
Q
Possible mechanisms: Hereditary and gender?
A
- certain inherited HLA types occur more frequently w/ certain immunological disorders: ex - 90% of pts w/ ankylosing spondylitis carry the HLA-B27 Ag
- the exact trigger that causes the autoimmune disease in pts w/ certain HLA types is unknown although there are some possible theories:
- certain viral or bacterial infections
- chemical substance exposure
- self Ag that has been hidden from immune system during development becomes released
- almost all autoimmune diseases are more common in women, therefore estrogen may play a big role
19
Q
Genes involved in SLE, Pathogenesis?
A
- HLA DR2 and DR3
- 85% of pts are female and more common in blacks (1:250) vs whites (1:1000)
- strong familial link: if mother has SLE than daughter w/ 1:40 chance and son w/ 1:250 chance
- produce autoabs to nuclear Ag
- multiple organ systems are affected
- many effects are secondary to trapping Ag-Ab complexes in capillaries of visceral structures
- other effects are autoab mediated destruction of host cells (thrombocytopenia)
20
Q
SLE enviro factors?
A
Hormones:
- females to males 15:1
- estrogen stimulates T cells, B cells, macrophages, releases some cytokines, and cell adhesion molecules
- estrogen increases macrophage proto-oncogene expression and reduces apoptosis in self reactive B cells
- androgens are immunosuppressive
- progesterone and prolactin affect immunoreactivity and favor autoab production
-UV light exacerbates the disease
- viruses can stimulate specific cells in immune network:
lupus flares may follow bacterial infections
Pts w/ SLE have higher titers to EBV
- some drugs can cause lupus like syndromes:
procainamide
hydralazine
21
Q
Pathogenesis of RA?
A
- genetic predisposition: assoc w/ HLA-DR4 and/or HLA-DR1
- disease is initiated by activation of helper T cells responding to some arthritogenic agent (possibly microbial)
- target is synovial lining of jts
- autoabs are produced against: Type II cartilage, cartilage antigenic glycoprotein-39, immunoglobulin G, citrullinated proteins and peptides
22
Q
Mechanism of RA synovitis?
A
- angiogenic cytokines stimulate growth of new blood vessels
- results in transudation of fluid into jt
- tumor necrosis factor (TNF) and substance P activate endothelial cells - produce adhesion molecules
- together w/ transmigration of lymphocytes, PMNs enter synovial space
- activated CD4 cells: activate macrophages and other cells, activate B cells producing Abs
- rheumatoid synovium has both lymphocyte and macrophage derived cytokines - cytokines (IL-1, TGF-alpha) also cause synovial and chondrocyte proliferation
- activated rheumatoid synovium eventually destroys cartilage and tendons
- simultaneously osteoclasts and osteoblasts are activated by synovial cytokines destroying subchondral bone
23
Q
Markers for RA?
A
- 70% of pts w/ RA are RF+
- autoabs (IgM and some IgG) are generated that are directed against the Fx portions of IgG
- RF and IgG form immune complexes that fit complement, attract neutrophils and lead to tissue injury
- circulating RF contributes to extra-articular manifestations of RA and synovial inflammation
24
Q
What is scleroderma? Who is it most common in? When? Types?
A
- diffuse fibrosis of skin and internal organs
- autoabs that stimulate platelet derived growth factor receptors (PSGFR) causing fibroblast deregulation
- 30-50s
- 3x more common in women
- two types:
limited (80%)
diffuse (20%)
25
Q
Characteristics of Limited Scleroderma?
A
- 80% of cases - limited to face and hands
- CREST syndrome:
Calcinosis cutis
Raynaud’s phenomenon
esophageal motility disorder
sclerodactyly
Telangectasias
26
Q
Characteristics of Diffuse scleroderma?
A
- 20% of cases
- tendon friction rubs over wrists, ankles, knees
- lung and cardiac involvement
- the more severe form
