(From Dr. Bohoeme’s Handout, 14 Sept 2000, by Brian Buschman)
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T-cells function in cellular immunity.
B-cells function in humoral immunity.
There are two types of TH-cells:
1) TH1 cells are helper T-cells that mediate delayed hypersensitivity reactions (Type IV hypersensitivity) as well as macrophage activation and IgG2b production. They secrete IL-2 and others but do NOT secrete IL-4 or IL-5.
2) TH2 cells are helper T-cells that ONLY secrete IL-4 and IL-5 and play a role in the production of all classes of Igs other then IgG2b.
CD40 is an essential intercellular signal for the interaction of B-cells with T-cells. Hence CD40 is essential for class switching. It’s shortage is sometimes a cause of hyper-IgM.
Macrophages are mononuclear phagocyte cells that process and present antigens and are essential in the cell-mediated immune system. They also phagocytize cells opsonized with IgG or C3b.
Dendrite (Langerhans’) cells are APCs of the dermis. Interdigitating dendritic cells act as pattern recognition receptors. Activation up-regulates lymphocyte action.
NK cells run around attacking all the cells opsonized by IgG. If the cell has MHC I it is recognized as self and NK cells do not kill it.
Lymphocyte growth, activation and differentation is up-regulated my IL-2,4,5,12 and 15.
Lymphocyte function is down-regulated by IL-10, IFN-g and TNF-a.
Inflammation is mediated by IFN-g and TNF-a.
MHC I has a1, a2, a3 and b2 subunits. Only the a3 is transmembrane. All but a1 have disulfide bridges to stabilize their loop.
MHC II has a1, a2, b1 and b2 subunits with both a2 and b2 being transmembrane. In MHC II all subunits have disulfide bridges.
Depending on who you talk to there is either four or five types of hypersensitivity. In the US we usually only talk about four types but in Britain they talk about type V which is a loss of function form.
Type I hypersensitivity is the anaphylactic type which is mediated by IgE which triggers mast cells to release their mediators. The excess of mediators causes the anaphylactic reaction.
It can be local or systemic. Systemic causes itching, hives, respiratory distress and such. It is the type you see with peanut allergies. Local has a topical response like a bug bite.
In the second type of hypersensitivity reactions the mediation is by IgG and IgM. They lead to the activation of mechanisms for cell lysis and death such as activation of the compliment system. They do it all without the use of inflammatory mechanisms. One example is myasthenia gravis with it’s Abs to the ACh receptors.
More examples include:
1) Goodpasture syndrome with abs that attack type IV collagen of the basement membranes of the nephrons and lungs. It leads to hemorrhage in the lungs and kidney.
2) Bullous pemphigoid has Abs to the epidermal basement membrane causing skin vesicles.
3) Pernicious anemia has Abs for IF and gastric parietal cells which causes shortage of vit. B12 and hence, megaloblastic anemia.
4) Vacuities has abs for neutrophils’ cytoplasmic antibodies.
5) Thrombotic phenomena has abs for antiphospholipid antibodies.
6) Acute rheumatic fever has abs for streptococcal Ags.
Part of type II hypersensitivity is ADCC, antibody dependant cell-mediated cytotoxin. ADCC is the lysis by NK cells when counted by IgG.
This is where IgG and C3b become important chemotactic mediators.
Type III hypersensitivity is similar to type II but it is mediated by immune complexes rather then antibodies. In type III the antibodies do respond to the antigen but they are used to produce the immune complexes. Then the immune complexes, like compliment, work to kill the cell.
Examples include farmer’s lung, SLE and arthritis. Again they can be either local or systemic.
The final type of hypersensitivity is mediated by CD 4 and CD 8 cells. No antibodies are needed in type IV reactions. The TH1 (CD 4) cells react in cause the DHR (delayed hypersensitivity response). These are reactions such as to poison ivy and such.
Cell mediated responses do not cause a problem with your first exposure to the Ag. The first exposure gets your immune system ready and with the second the reaction occurs. This is the case in bee stink allergies.
As a refresher the TH1 cells, not the TH2 cells, mediate type IV hypersensitivity. They produce only IL-4 and IL-5 and create IgG2 but not other antibodies.
There are two T-cell mediated mechanisms of transplant rejection. The direct and indirect mechanisms.
1) In the direct mechanism T-cells of the recipient find their antigens on the APCs from the donor organ. That is the APCs and were transplanted with the organ show off pieces of them to the recipient T-cell system. They directly fight the transplanted organ.
2) In the indirect system recipient APCs go and grab pieces of the donor tissue and present it to their T-cells. This is indirect because it requires two steps where the direct mechanism does not.
Acute rejection happens within days after transplantation and is mediated by both cellular and humoral tissues. The rejection includes necrotizing vasculitis which is an inflammation of the blood vessels with fibrotic necrosis.
Chronic rejection is seen as proliferative and occlusive arthritis.
Central tolerance is due to clonal deletion of self-reactive T and B-cells during maturation in the thymus and marrow. It’s main mechanism is via apoptosis.
Peripheral tolerance refers to clonal anergy because second signals during antigen presentation cannot be generated.
We have no evidence that autoimmune disease is caused by failure of the central immuno-tolerance system. It can be caused by:
1) Failure of T-cell mediated immune suppression.
2) Polyclonal activation.
3) Failure of activation induced cell death.
There is a large familial link to autoimmunity. Strong HLA links exist but autoimmune diseases are multifactoral as best we know.
Microbial products can play a role by a few mechanisms in creating autoimmunity. Viruses may show-off domains for presentation which are similar to self and cause self-antibodies to be produced. Superantigens may activate too many T and B-cells causing obvious problems. (See Immuno notes, irregulation.html, for more info on superantigens.)
Systemic lupus erythematosus is an autoimmune disease of antibodies to DNA. Specifically towards dsDNA, but also to DNA related proteins like histones. These antibodies form from a breakdown in the mechanism of self tolerance.
Symptoms are acute effects towards the skin, joints, kidneys and serosal membranes. They attacks are acute but they come and go and become a chronic pattern. SLE can be identified by:
1) A malor rash which is the characteristic “butterfly” rash of SLE on the face.
2) Discoid rash which is a round scaly rash over any part of the body.
3) SLE patients are very photosensitive.
4) Oral ulcers can be seen.
5) It is accompanied by arthritis in peripheral joints with tenderness and swelling.
6) Serositis is an inflammation of the pleura (pleuritis) or pericardium (pericarditis).
7) Renal disorders like persistent proteinuria.
8) Neurological disorders like seizures and psychosis.
9) Hematologic disorders like leukopenia, lympophenia, thrombocytopenia.
10) Immunologic disorders because of the anti-DNA.
11) ANA – Antinuclear antibodies can be seen.
There are several forms of SLE:
1) Chronic discord lupus erythematosus has prevailing skin lesions but systemic legions and Ab to dsDNA are absent.
2) Subacute cutaneous lupus erythematosus has widespread cutaneous legions not associated with scarring. It also presents with ssDNA antibodies and HLA-DR3.
3) Drug induced lupus erythematosus can be caused by D-penicillamine, isoniazide and procainamide.
Sjoegren’s syndrome is an autoimmune destruction of lacrimal and salivary glands. It causes xerostomia (dry mouth) and keratoconjunctivitis (dry eyes). It is associated with an increased risk of lymphoma.
A disease where small vessels undergo fibrosis systemically. It has CD4 cells that respond to unknown antigens.
Skin and muscle inflammation. Rashes and progressive muscle weakness develop.
Proximal muscle weakness without the skin infection of dermatomyositis.
An asymmetric involvement of distal muscles.
Inherited inability for B-cells to mature. This causes a lack of ability to properly produce gammaglobulin for the production of Igs. Hence a patient is lacking the mechanisms of humoral mediated immunity. The patient has some initial humoral mediated immunity after birth from the IgG that came from the mother but after a month they must be treated with gammaglobulin so they can make their own.
Patients with agammaglobulinemia are still able to respond to virally infected cells because the T-cell system is still intact.
DeGeorge’s is a problem with the development of the 3rd and 4th pouches which leads to an underdevelopment of the thymus which causes a loss of cell mediated immunity (no T-cells produced).
DeGeorge’s is often accompanied by a common truncus arteriosus (the pulmonary artery and aorta never divided) which leads to cyanosis and death.
Blood transfusions are needed but the blood must be radiated first so that the patient does not have cell mediated immunity to itself (from the new leukocytes) but that also defeats part of the purpose.
SCIDS is a loss of both T-cell systems and B-cell systems. Children present with vomiting, diarrhea, and such. The only real hope is a marrow transplant. It can be either x-linked recessive or autosomal recessive.
It is x-linked recessive leading to early death from a combination of three problems. They present with ahrombocytopenia, immunodeficiency and eczema (scaly rash).
A retroviral disease with immunosuppression causing secondary infections and neoplasms and neurological manifestations.
Immune abnormalities include lymphopenia, decreased and altered T-cell function and polyclonal B-cell activation. I find it interesting to see decreased T-cell with B-cell activation.
Kapossis sarcoma is a neoplasm caused by the herpes virus 8 which is common in aids.
Other AIDS related malignancies include Hodgkin’s disease, B-cell lymphoma, carcinoma of the uterine cervix and cancers of the GI, lung and salivary glands.
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