Immunology: Chapter 15 Flashcards
(19 cards)
Nature of Immune responses to self
No direct means to distinguish between self and non self
Some self-reactive lymphocytes do mature and can become activated to cause autoimmune disease
If Immune system excluded ALL lymphocytes, with even slightest degree of self-reactivity, it would be impaired.
Either antibodies or T cells may predominate (usually multiple effector function in autoimmune disease)
Injection with self antigens mixed with strong adjuvants containing bacteria –> autoimmune disease
Internal dysregulation of immune system
B AND T cells
Organ-specific autoimmune diseases
Type I diabetes mellitus
Insulin producing beta cell’s pancreatic islets are destroyed by combined T cell and B cell response
T cells play predominant role
Systemic autoimmune disease
Systemic lupus erythematosus (SLE)
Antibodies produced to antigens are ubiquitous and abundant in every cell in body
Ex: antibodies to DNA, histones, ribosomes, and RNA splicing machinery
Combined T cell and B cell response
Dominant role for antibodies
Typical autoimmune disease
Initial loss of tolerance and autoimmunity may evolve to chronic disease state b/c of positive feedback from inflammation + inability to clear self-antigen
Antigen can never be eliminated
Exception: Type I diabetes, the beta cells of the pancreas are completely destroyed by T cell response
Continued presence of antigens –> chronic inflammation, (release of more autoantigens) tissue damage, and continued self-destruction
Strong Genetic component
Autoimmune disease tends to run in families
Tends to be more common in women than men
You will not necessarily develop an autoimmune disease if you have an affected identical twin
Genes predisposing to autoimmunity
Affect auto-antigen availability and clearance
Involved in cytokine gene expression
Affecting expression of co-stimulatory molecules
MHC genotype- (role in controlling susceptibility)
Certain MHC alleles may present auto-antigenic peptides to auto reactive T cells (If you don’t have the MHC allele, you can’t present the auto reactive peptide)
Ability of T cells to respond to antigen depends on MHC genotype
Autoreactivity
Susceptibility to autoimmune disease is determined by differences in ability of different allelic variants of MHC molecules to present auto-antigenic peptides to auto reactive T cells
Identical twins are far MORE likely to develop the same autoimmune disease than MHC-identical siblings
Hypersensitivity: Type I IgE-mediated responses play major role
Autoimmunity: IgE antibodies are NEVER
Sex differences
Sjogren’s syndrome, lupus, thyroid disease (Hashimoto’s thyroiditis and Graves’ disease) and scleroderma affect >80% women
Rheumatoid arthritis (RA), multiple sclerosis (MS) and myasthenia gravis affect 60-75% women
Sarcoid, ulcerative colitis, and Type I diabetes affect ~50% women
Type I diabetes: 50%:50% men and women
Women have heightened immune responses (for childbearing?)
After immunization, female mice produce more antibody and show more vigorous T cell activation than males
Have higher CD4 lymphocyte counts than men
Higher proportion of TH1 cytokines under conditions of immunization
Pregnancy
Estrogen, progesterone and a TH2 environment increase greatly during 3rd trimester
MS and RA (TH1 response) decrease during pregnancy, then flare up after birth (Both TH1-oriented) should get better
Hormone levels fall after birth and TH1 environment sets in
SLE (lupus) is worse or unchanged during pregnancy, but may improve after birth (TH2- and antibody-oriented)
Vitamin D and multiple sclerosis
Most prevalent in northern countries
Vitamin D supplementation reduces the frequency of MS
Dependency of the frequency of MS with the month of birth
May babies have the highest likelihood of developing MS later in life and November babies have the least likelihood
Low levels of wintertime vitamin D levels at some critical point of brain or immune system development, either during gestation or shortly after, increases the risk of later development of MS
Vitamin D and type I diabetes
African American ancestry is more likely to be deficient in Vitamin D and more likely to develop type I diabetes
Children in Finland receiving Vitamin D supplements (1,000 IU per day throughout childhood, and then followed for the next 30 years) were 75% less likely to develop type I diabetes
Vitamin D and disease
Associated with better resistance to infectious disease
A. American women receiving 2000 IU per day had 93% reduction in upper respiratory tract symptoms
Suboptimal levels may be one of the reasons that flu and other infectious diseases are more prevalent during winter months
Vitamin D and TB
Inhibit formation of phagolysosomes involving glycosylated phosphatidylinositol lipoarabinomannan (compound of bacterial membrane)
Lipoarabinomannan is translocated to phagosome wall of macrophage, interrupting the normal maturation of the phagosome and its further fusion with the lysosome
Bacilli also inhibit Ca++ signaling events
Activates pathway involving phosphatidylinositol-3-kinase that completely reverses inhibition phagolysosome formation, leading to destruction of tuberculosis bacilli
Vitamin D is also required for synthesis of potent antimicrobial peptide of the cathelicidin family, LL-37
Solariums and higher altitudes increase levels of vitamin D
Graft rejection
Immunological response mediated primarily by T cells
Autographs (same person) = 100% success
Syngeneic (identical twins) = 100% success
Allogeneic (genetical different indiv.): rejected 10-13 days after grafting (first-set)
Seond graft- same donor- rejected in 6-8 days (second-set)
*****Rejection of allogeneic grafts: donor dendritic cells present donor antigens to host T cells, which mount an immune response and destroy the graft
HLA (tissue) matching
Try to match MHC types, but is not very successful
Reason #1: individuals who type as identical only rarely have identical MHC genotypes bc the antibodies used for typing do not distinguish all differenced
Reason #2: Other genetic differences (will generate other antigenic differences called “mini H antigens”) lead to slow, but sure rejection
Only grafts between identical twins work- all others must use immunosuppressant drugs
Graft-versus-host-disease (GVHD)
Converse of graft rejection
Mature T cells from the graft (donor T cells) are incompatible with recipient cells –> mount a response
Problem with allogeneic bone marrow transplants
Severe inflammatory disease
Solution: eliminate donor T cells from the donor bone marrow before transplantation.
New T cells will go through the host’s thymus during development and are tolerant to host antigens
Preexisting antibodies
Cause immediate rejection of transplanted organs
Vessels become blocked, graft becomes purple-colored from hemorrhaged blood (becomes deoxygenated)
Certain, hyperacute rejection
Prevents the routine use of animal organs as donors (xenografts): won’t work b/c we carry preexisting antibodies to animal antigens
Modern immunosuppressive drugs
~85% of cadaveric kidney grafts are still functioning one year later (highest graft survival)
Half-life for survival of renal allografts remains at 8 years
