Lecture 18-19 - T4-HS & Autoimmunity Flashcards
T4HS mediators (immune reactants)
TH1, TH2, and CTL
T4HS Antigens are ____ and ____
(Which go with which?)
Soluble and Insoluble
(cell-associated antigen –> CTL)
(Soluble –> Th1 and Th2)
Three syndrome-types caused by T4HS
Delayed type HS (PROTEINS)
Contact Type HS (HAPTENS)
GIT Disease (Gliadin)
**all involve T cells
Causative agent for Poison ivy
pentadecacatechol
First encounter causes ____
sensitization
Steps of a “first encounter” sensitizing process
- skin penetration
- modification of self proteins
- Ag captured by APC, presented in LN
- (in LN) Activate T cells and generate specific T cells)
- –> leads to asymptomatic response
Later encounter of Ag results in ________
hypersensitivity reaction
- Same first steps as first response (skin, mod’ self proteins)
- Presented in LN and in skin
- Memory Tcells are activated
- Activation of downstream effectors and phagocyte recruitment
- DC’s in epidermis
- DC’s in afferent lymphatic
- DC’s in LN
- Langerhans
- Veiled cell
- Interdigitating DC
Lymphocytes found in skin express what three things
- CLA (cutaneous LC antigen)
- P/E selectin ligands
- chemokine receptors (CCR4/8, CCR10)
Skin DTH reaction steps
- penetrates skin
- taken up by langerhans
- present self peptides (haptenated with the agent) to Th1 cells (secrete IFN)
- keratinocytes secrete cytokines and chemokines (secrete IL1, TNFa, etc)
In skin DTH reaction, naive T cells are matured to Th1 cells in…
Lymph node
Th1 cells secretions and their effects
- Chemokines = MQ recruitment
- IFNgamma = Activates MQ
- TNFa and LT = Local tissue destruction
- IL3 & GM-CSF = Monocyte productions by stem cells in BM
Tx for Contact HS
Corticosteroids
(suppress inflammator genes, induce synthesis of anti-inflamm proteins)
Examples of DTH
Tuberculin skin test
Poison ivy
celiac
chromic asthma (Th2)
How to we get immune tolerance to self (B cells?)
B cells anergized or deleted in bone marrow, periphery, germinal centers
How do we get immune tolerance to self (T cells)?
- Autoreactive T cells are deleted in the thymus
- Autoreactive T cells are anergized or deleted in the periphery
5 ways to gain immune tolerance to prevent autoimmunity
- Delete or anergize B cells in BM, periphery, or GC’s
- Delete T cells in thymus…..Anergize or delete T cells in periphery
- Supress Treg (CD4+CD25+)
- Physically separate tissue Ag from immune cells
- Limit MHC2 and B7 expression (reduces activation)
Susceptability factors in AI diseaes
- HLA genotype
- Microbial infection
- injury
- environmental factors and behavior
- gender/sex hormones
Three ways microbial infection increases AI risk
- Adjuvant effect: recruitment and activation of immune cells
- Induction of MHC molecules and B7
- Molecular mimicry
Sympathetic Ophthalmia
Physical trauma in one eye initiates AI in both
- eye anterior is IMMUNE PRIVILEDGED SITE
- Injury in one eye drains to LN
- Immune response of effector T cells
- return to BOTH eyes to react and cause damage/blindness
Most AI diseases affect ___
Which ones dont?
Females
- Psoriasis, UC, AI uvitis, Bechets* hit both equally
- (Ankylosing spondylitis* = males)
What is APECED? What is deficient? What diseases result?
AI polyendocrynology candidiasis ectodermal dystrophy
Mutations in AIRE (AI regulator) gene = Defective Thymic deletion because inability to express peripheral antigens in thymus
Endocrine = Hypoparathyroidism, adrenal failure, ovarian fail
Other = Candidiasis (100%!), Dental enamel hypoplasia, nail dystrophy
IPEX is a _____mutation
FOXP3
(essential for generation of Tregs –> inflamed small intestine)
“immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome”
Celiac CD4 T cells specific for…
How does this happen?
What ends up being made?
gluten peptide
DQ2 and DQ8 present the peptide to CD4 T cells
Anti-transglutaminase autoantibodies = destruction of villi
Molecular mimicry main cause (molecularly)
Same MHC moleucle presents both a pathogen peptide and a self peptide that mimics it
Effector TH1 cell responds in the same way it would to the pathogen, activating MQ
Infection induces ____ production, which increased _____ expression on tissue cells
IFN gamma
MHC class 2
**results in T cell activation and AI
AI hemolytic anemia (Type 2) initiation, steps, and treatment
RBC’s bind to antiRBC autoAB’s
- FcR cells in spleen –> phagoc.
- complement activation and CR1 cells in spleen –> phagoc.
- complement activation and Intravascular hemolysis = Lysis
Splenectomy reduces RBC loss
Immune Thrombocytopenic Purpura (ITP)
What do antibodies attach to?
Half-ish cases are classified as _____
antobodies attach to blood platelet for destruction
half are idiopathic
Goodpastures syndrome is IgG against…
Alpha-3 chain of Type 4 Collagen
(present in basement membranes of lung, kidney, etc) = infiltration with PMN and MNC
Tx = plasma exchange + immunosuppressants
Graves disease antibodies effect?
Sx?
Tx?
autoantibodies are STIMULATORY to the TSH receptor
leads to increased thyroid hormone = hyperthyroid diseases (heat intolerance, nervousness, weight lost, thyroid enlargement)
Tx = thyroidectomy or radioactive destruction with 131Iodine
Vertical transmission of antibodies in Graves disease (with treament)?
- Mom makes anti TSH receptor AB’s
- Crosses placenta
- Newborn has disease
- Plasmapheresis removes moms AB’s and cures
Hashimoto’s pathology?
Tx?
ABs and effector T cells against thyroid
(TH1 mediated)
Tx = oral administration of thyroid hormone
IDDM autoantibodies attack
Islet cells in Pancreas = no insulin
SLE involves AB’s to ____
What causes the symptoms (rash, etc..)
DNA and histones
Immune complexes form and get deposited in BV, kidney, joints etc
Rheumatoid factor =
Produced by ______
IgM, IgG, or IgA against the Fc region of IgG
Produced by Plasma B cells
Pathology behind RA
Tx?
- Leukocytes infiltrate the joint synovium (CD4/8 and B cells, PMN, MQ)
- Inflammatory cells make PG’s, LT’s, enzymes and collagenases
Tx = anti-inflammatories, immunosuppressive drugs
(like anti-TNFa)
What effect does smoking have on RA
- generates CITRULLINE residues = CD4 activation
- increases peptidylarginine deiminase 2 expression
*causes peptides with citrulline residues to be presented to CD4 Tcells (by HLA class 2)
Tx for RA
Anti-CD20
reduces the interaction of CD20 on B cells with FcgRIII receptor on NK cells (stops killing)
GBS tx
plasmapheresis and high dose IVIG
MS is a response against _____
_____ cells are implicated. What is their effect?
Treatment = ?
against myelin
Activated T cells (Th17 or Th1) = induce expression of chemokines/cytokines that recruit the demyelinating inflammatory cells
Tx = IFN-beta injections (suppress Th17), immunosuppressants, Natalizumab
Natalizumab is anti ______ treatment for _______
anti-VLA4/integrin
Tx for MS
What is the role of CNS inflammation in demyelination
Generation and migration of CNS specific T cells causes IL17 and IFN gamma to be released
Astrocytes and microglial cells are activated by leukocytes
MS drugs and targets
Daclizumab = IL2Ra and T cell activation
Natalizumab = a4 integrin and T cell migration
Fingolimod = T cell migration
Azathioprine = T cell proliferation
Methotrexate
Rapamycin = mTOR
Myasthenia Gravis Tx
Pyridostigmine (cholinesterase inhibitor)
Azathioprine (blocks T cell proliferation = immunosuppressant)
Thymectomy
