Chapter 6 Pt 2 Flashcards
What causes type IV hypersensitivity?
Inflammation resulting from cytokines produced by CD4+ T cells and killing by CD8+ T cell
What causes type IV hypersensitivity?
- Rheumatoid arthritis
- Multiple Sclerosis
- Type I DM
- Inflammatory bowel disease
- Psoriasis
- Contact dermatitis
What is the classic example of a Delayed Type Hypersensivity?
How does this work?
- Tuberculin reaction
- Purified protein derivative (PPD; aka tuberculin), a protein-containing Ag of the tubercle bacillus is injected intracutaneously.
- Previously sensitized pt’s will have reddening and induration of the site appear in 8-12 hrs and peaking at 24-72 hrs
T-cell mediated type 4 hypersensitivity can occur in what 2 processes
- CD4+ T-cells: Delayed type hypersensitivity
2. CD8+ T cell mediated cytotoxicity
Which T-cells usually are responsible for delayed type hypersensitivity?
Th1
Th17
If APC’s produce IL-12 which T helper cell will CD4+ T cells differentiate into?
How about if they produce IL-1, IL-6, and IL-23?
- IL-12 —> TH1 —> IFN-gamma —> more TH1
- IL-1, IL-6, IL-23 —> TH17
Inflammation produced in psoriasis is mediated mainly by cytokines produced by?
What type of hypersensitivity is this?
- TH17
- T-cell mediated (Type IV) hypersensitivity
Activated TH17 cells produce which cytokines and how do they contribute to the inflammatory response of typer IV hypersensitivities?
- IL-17, IL-21, IL-22, and chemokines
- Collectively, recruit neutrophils and monocytes to the rxn, thus promoting inflammation
- IL-21 amplifies the TH17 response
What is the predominate infiltrate in the lungs after 2-3 weeks of a tuberculous infection?
Sustained activation causes these cells to undergo?
What then occurs?
- Macrophages
transform from MO=> epitheloid cells, which will be surrounded by collar of lymphocytes, and referred to as a granuloma=> granumomatous inflammation.
Granulomatous inflammation => + Th1 cells => make IFN-y
Granulomatous inflammation is associated with strong _____ activation and high-level of cytokines such as _____.
Granulomatous inflammation is associated with strong TH1-cell activation and high-level of cytokines such as IFN-gamma
Contact dermatitis is tissue injury resulting from what type of reaction?
How do these substances cause a rxn?
- Delayed-Type Hypersensitivity (4)
Environmental chemical (e.g. urushiol from poison ivy, nickel) binds to and structurally modifies self-proteins, which are recognized by T-cells and cause inflammation of skin (vascular dermatitis)
What are the 2 most important types of tissue injury seen in CD8+ T cell mediated cytotoxicity?
- Type 1 DB
2. Rejection of graft after organ transplant
Dysbiosis is implicated in which diseases?
IBD
Allergy
Autoimmune diseases
Autoimmune diseases affect at least _____ of the population, men or women more?
They are caused by the loss of what?
1-2%
Women»_space;> men
loss of self tolerance; body will attack self-antigens
The presence of autoantibodies does or does not, mean we have an autoimmune disease?
Presence of autoantibodies ≠ autoimmune disease.
At least 3 requirements must be met before a disease can be considered autoimmune
- Rxn to a self-antigen
- Rxn is not secondary to tissue damage, rather, it CAUSES tissue damage
- Other causes are ruled out
How do AI diseases manifest? (3)
- organ specific: type 1 DM or MS
- systemic: SLE
- Neither: goodpasture syndrome: AB in basement membrane of lung and kidney cause lesions
Autoimmune diseases are formed when lymphocytes that recognize self-antigens escape both central and peripheral tolerance.
What is central tolerance; how can it prevent AI?
What is peripheral tolerance; how can it prevent AI?
Central tolerance: catches immature lymphocytes in BM and thymus that recognize self-antigens and:
- Apoptosis
- Become Treg cells
- B cells undergo receptor editing (RAG)
if they escape: another chance
Peripheral tolerance: catches mature lymphocytes in peripheral tissue and
- Apoptosis
- Inactive (anergy)
- Suppressed by T-reg cells
What are the 3 immune-privileged sites?
brain
eyes
testis
hard for immune reactions to antigens to occur here bc they dont communicate with blood or lymph
AIRE is responsible for inducing the expression of what?
.
Mutations in AIRE: cause
What normal processes would fail?
expressing self antigen
autoimmune polyendocrinopathy
ability to express self-antigens
What is CTLA?
What is the opposite of CTLA4?
Inhibitory receptor on T-reg that bind to CD80/86 on APC => prevent activation of the T cell to avoid immune repsonse
CD28 is a activator on T-cells that bind to CD80/86 on APC => activate the T cell => cause an immune response.
What has a higher affinity for CD80/86 (B7): CTLA4 or CD28?
CTLA4
PD-1 on T-cell
binds to
PD-L1 on the APC
what hpapens?
supresses T-cell
Cancer is treated with anti-CTLA4 and anti PD1 antibodies that do what
prevent binding of CTLA-4/CD80
and PD1-PDL1
so that we can + our immune response to cancer cells => prolonged tissue inflammation and injury
What is a T-reg cell
what cytokines is NECESSARY for maintance of T-cell?
CD4+
CD25+
FOXP3+
IL-2
how does anergy occur?
- Inactivates self-antigen when there is not enough co-stimulation
- Induces anergy by using inhibitory receptors (CTLA-4 or PD1)
Peripheral tolerance
- anergy (inactivation)
- T-reg do what?
- Apoptosis
Suppress to prevent reaction against self-antigens
Generating T-reg cells requires what?
Maintaing T-cells requires what?
TGF-B
IL2 and FOXP3
What are the 3 ways that T-reg cells supress immune responses against self antigens?
- Secrete IL-10 and TGF-B
- Express CTLA-4
- Protect fetal Ag inhereitas from dad
mutations in FOXP3 cause what
IPEX (immune dysregulation polyendocrinopathy, enteropthy, X-linked)
=> causes systemic diseases
How does apopotosis occur in peripheral tolerance
If self reactive
- Express Bim (+apoptosis) => intrinsic patheay
- FasL/Fas path
FAS gene mutation causes what
Autoimmune Lymphoproliferative Syndrome (ALPS)
TREG cells are important in maintain _____ tolerance to the developing fetus, which have _____ antigens (which is 50% foreign
maternal
paternal
How do you develop AI diseases?
- Inherit a susceptibility gene
=> cause loss of tolerance and produce self-reactive lymphocytes.
However, this self-reactive lymphocyte cannot crease an AI disease: it needs to expand and activate.
Thus, to expanc and +; it needs and ENVIRONEMTNAL trigger (ex. molecular mimicry, epitope spreading)
Env trigger will active the self-reactive lymphocyte, which can
- Cause defective tolerance
- abnormal display of self-anitgens
- inflamm and initial innate immune response
Once induced, autoimmune diseases tend to be ____, ____, with occasional relapses and remissions d.t the immune system ________.
chronic, progressive
allowing some cells to overcome infection
what is epitope spreading?
ex?
- immune response attacks self-tissue => damages => releases more self-ag
- however, these new self-ag escaped tolerance and were not presented to T cells
=> cause an immine responses
=> cycle of persistant AI
ex. oral lichen planus
Most chronic inflammatory diseases are caused by abnormal or excessive_____________ repsonses
Th1
Th17
Systemic diseases tend to involve blood vessels and connective tissues.
BV
CT
Ankylosing spondylitis is a heredity inflammation of the joints, particularly the spine. This leads to degeneration and fusion of the vertebra.
what inherited suscepibility gene did someone with ankylosing spondylitis inherit?
if they have it, do they have AS?
does evyerone with AS have suscpebility gene?
MHC Class I
HLA-B27 (05/02)
no
no
What diseases are assx with ppl who inherited susceptibility gene
HLA- DRB?
- Rheumatoid arthritis (RA)
- T1DM
- MS
- SLE
what inherited suscepibility gene did someone with celiac disease inherit?
HLA-DQA1
Which gene is said to be MOST frequently implicated in autoimmunity; encodes what?
Associated with what disorders?
- PTPN22; encodes a protein tyrosine phosphatase
mutation: defective TP => cant control TK => + lymphocyte
Type I DM,
Rheumatoid arthritis
IBD
Polymorphisms in the gene for ____ are associated with what Chrons disease?
NOD2
what is the NOD2 gene?
NOD2 is a cytoplasmic sensor that detects microbes.
If mutated, Paneth cells in the intestinal epithlium are cannot kill commensal bacteria => increase of bacteria => BIG immune response
Polymorphisms in gene encording for
CD25 (IL-2R) and IL-7 are assox with with?
MS
Type I diabetes
What are 2 methods by which infections may induce autoimmunity?
1) Infections may upregulate the expression of co-stimulators on APCs; if these cells are presenting self-antigens result may be a breakdown of anergy and activation of self-reactive T cells
2) Molecular mimicry: microbe expresses Ag w/ same AA sequence as self-Ags
What is the classic example of molecular mimicry?
Causes what?
- Rheumatic heart disease; Abs against streptococcal proteins cross-react w/ myocardial proteins
- Cause Myocarditis
How may infections actually protect against some autoimmune diseases?
Promoting low levels of IL-2 production which is essential for maintaining Treg cells
Presence of ANA (anti-nuclear AB) is used to detect the presence of ADS.
If (-), =>
. If (+), _____
person does not have a disease
perform a more specific test, becase ANA is a sensitive test for MULTIPLE autoimmunse desases
What ANAs are specific for lupus, that are virtually diagnostic?
Anti-dsDNA
Anti-smith
What antibodies are diagnostic for Sjogren syndrome?
Anti-Ro/SS-A
Anti-La/SS-B
Autoantibody associated with diffuse systemic scleroderma?
Limited systemic scleroderma?
Anti-DNA topoisomerase (Scl-70)
Limited (CREST): anti-centromere AB
SLE is a AD that involves multiple organs (skin, joints, kidneys and serosal membrane, but virtually every other organ can be affected) characterized by MANY. autoantibodies
Injury in SLE is caused by?
What type of hypersensitivity?
- Deposition of immune complexes and binding of antibodies to various cells and tissues
- Type III hypersensitivity
Hallmark of SLE:
production of autoantibodies (especially ANAs)
will also have
- Ab directed against BCs
- antiphospholipid Ab
What group of people is most common to develop SLE?
W
AA/hispanics
Patients with SLE that have the presence of antiphosphlipid antibodies (30-40% have), particular lupus anticoagulant, will have increased?
These antibodies cause what kind of state?
- falsely high PTT
- Hypercoagulable state (excessive clotting); leading to thrombosis
Specific alleles of which HLA has been linked to production of anti-dsDNA, anti-Sm, and anti-phospholipid antibodies seen in SLE?
HLA-DQ
What environmental factors are involved in SLE?
- UV light= > increases apoptosis, cause keratinocytes to make IL-1, alter DNA
- Gender bias: F are more likely because of estrogen and genes on X crhomosome
- Drugs: such as hydralazine, procainamide, and D-penicillamine; once taken away, sx go away
Congenital deficiencies in complement components (i.e. C2, C4, and C1q) may impair immune complex clearance and favor tissue deposition.
Knockout mice for ___ are prone to develop lupus-like autoimmunity
C4
Most characteristic lesions of SLE affect the:
BV, CT, kidney, skin
What is the morphology of the blood vessels like in patients with SLE?
How about in the chronic stages?
- Acute necrotizing vasculitis involving capillaries, small arteries, and arterioles
- Chronic stages = vessels undergo fibrous thickening with luminal narrowing
What are the joints like in patients with SLE?
Opposite of what?
- Non-erosive synovitis with little deformity
- Opposite of RA
Kidney lesions in SLE are the result of what?
how many ppl have kidney problems?
immune complex deposition in the mesanguim/BM of glomerulus
50%
What is the most common and also the most severe pattern of glomerular disease seen in SLE?
Characteristics/morphology?
- Diffuse lupus nephritis (Class IV)
- > 50% involvement of Glomeruli
1. symptomatic; protein/hematuria
2. Increased cellularity: Proliferation of epithelial cells —> lateral crescents that fill Bowmans space
3. immune complexes deposit in the subendothelium => thickening of capillary wall, forming “wire loop” structures on light mircoscopy (see attached photo)
What is the 1st pattern of glomerular dz we see in SLE?
last?
- minimal mesengial lupus nephritis first
2. sclerosing lupus nephritis; sclerosing is an end-stage process.
