BL.2.1: Immunodeficiency, Type IV immunopathology Flashcards
Characterize the infections you would expect in a pure B cell deficiency and in a pure T cell deficiency.
T deficiencies are associated with severe infections with intracellular pathogens, including viruses, certain bacteria, and yeasts and fungi, especially Candida albicans and Pneumocystis carinii (whose new name is P. jirovecii). B cell deficiency is characterized by infections with “high-grade” (extracellular, pyogenic = pus-producing) bacterial pathogens such as Staphylococcus aureus, Haemophilus influenzae and Streptococcus pneumoniae. All of this makes good sense if you remember antibody and T cell-mediated mechanisms.
Describe the clinical features which, although not immunological, are associated with DiGeorge syndrome.
Unexplained convulsions in infancy, treated with calcium, viral and fungal infections common. Also, they have hypertelorism, down-slanting eyes, fishmouth deformity, micrognathia (undersized jaw), and low-set ears.
Discuss the incidence of selective IgA deficiency, and the associated syndromes.
SELECTIVE IGA DEFICIENCY is the most common immunodeficiency disease, with a frequency of about 1 in 500. Although it is usually asymptomatic, the patient may have diarrhea and sinopulmonary infections, or an increased frequency and severity of allergies. There is a familial tendency, and although several mechanisms have been proposed, none is yet clearly established. It is 10-15 times more frequent in people with celiac disease.
Describe the immunological problem of the Nude mouse, and name the human immunodeficiency condition it resembles.
Nude mice have quite a different mutation, but also fail to make a thymic stroma (and hair) and so they have no T cells, and are immunologically similar to DiGeorge kids.
Name the enzyme which is absent in some cases of SCID. Discuss possible approaches to replacing this enzyme.
Most of these patients lack the enzyme adenosine deaminase (ADA); adenosine accumulates in all cells but apparently impairs lymphocyte development most severely. Rarest globally are defects in the Rag V(D)J recombination machinery, although that is the most common form of SCID in Navajo children.For SCID, bone marrow transplantation has about a 50% success rate, but graft-versus-host disease is always a problem. It is better to transplant purified stem cells than whole bone marrow. Sibling donors are the best, and a good Class II MHC match is imperative. For ADA- deficient patients, transfusions of irradiated red cells can be helpful. Purified ADA, stabilized with polyethylene glycol (“PEGylated”), is also available for use as a drug.
Discuss transplantation therapy in immunodeficiency diseases. Include a consideration of side effects.
Can do bone marrow transplant for SCID: graft vs. host disease can result.In DiGeorge, fetal thymus or cultured thymic stromal cells have been used to try to minimize the risk of graft-versus-host disease. Some success is claimed; better diagnosis would aid in the selection of appropriate cases.Gene therapy SCID kids have developed cancer - possible side effect.
Given a child with recurrent infections, describe in principle tests which could be done to determine if there is a T, B or combined immunodeficiency, or a PMN, macrophage or complement problem.
- History2. Physical exam3. Test integrated systems –> limited, also cheap and easy –> expensive and painful.
On a diagram of a lymph node, label T and B cell areas.
Bottom photo, B-cells outside (in follicles and such) T-cells fill the middle.
Describe the contents and routes of administration of commercial gamma globulin and indicate the conditions in which it can be useful replacement therapy.
Human immunoglobulin, where B cell function is deficient.This must be given approximately monthly. It is pooled from many donors, and is usually about 99% IgG, with a half-life of 3 weeks.There is a form for IV use (IVIg) from several manufacturers; effective but expensive, and often in short supply.Recently, a preparation for slow subcutaneous infusion that can be done at home has been approved.Caution must be used if giving replacement immunoglobulins to people with selective IgA deficiency. The IgA in the preparation may be foreign to them, provoking an allergic or immune complex reaction.
Name two viruses which are immunosuppressive in humans. Discuss a possible mechanism for the immunosuppression caused by one of these viruses.
Many viral illnesses, especially measles, mononucleosis, and cytomegalovirus (CMV) infection, are immunosuppressive, and secondary infection is common. Acquired Immune Deficiency Syndrome or AIDS is the most serious condition involving secondary immunodeficiency.
Define Type IV immunopathology.
“T cell-mediated” or “Type IV” mechanisms are just immune system events that can be harmful or great and involve T cells. . They are the only type of immunopathology (of Types I, II, III and IV) which do not require antibody or B cells (strictly speaking).
Describe the cellular and molecular events that take place in a positive skin test for tuberculosis. Explain why this reaction is called delayed-type hypersensitivity.
The Mantoux skin test is most commonly used in the USA. In it, 0.1 mL of PPD—purified protein derivative, a standardized preparation of M. tuberculosis antigens—is injected intradermally. The antigen is taken up by local macrophages and dendritic cells, and presented on MHC Class II. If the subject has an increased number of anti-tuberculosis Th1 cells, they will come by and get stimulated, produce IFNγ, and attract macrophages. The test is read at 48 hours, and the diameter of the induration (firm raised part) is measured; 15 mm is always positive, and 10 or even 5 mm can be called positive under certain conditions, for example if a person is partly immunosuppressed.â–ºmemory T cells from the expanded clones are throughout the body, and get activated in the area where the TB has been deposited. They secrete interferon-γ which attracts and activates a large number of macrophages. The result is a firm red area of inflammation that, because of all the cellular events that need to take place, begins to be visible in 6 to 12 hours, and peaks at 24 to 48 hours, thus earning the label â–ºdelayed- type hypersensitivity.
Explain why a person usually has no observed symptoms when first exposed to poison ivy.
Consider poison ivy, an example of contact dermatitis due to the oil of Toxicodendron (formerly Rhus) radicans. It contains the compound urushiol which can penetrate the skin and become associated with MHC on dendritic cells (either by binding directly to MHC, or by binding peptides which then get presented on MHC). The dendritic cell leaves the skin and travels to the draining lymph nodes, where it presents its MHC to the appropriate Th1 cells. These begin to divide in the usual way, but by the time increased numbers of them are in the circulation, the antigen has been washed or worn off the skin, and there is no reaction. So at the time you became immunized (“sensitized”) you probably didn’t know it happened.
Discuss how a chemical or small peptide might not need to be processed through an antigen- presenting cell to be presented by that cell to T cells.
It could be attached to an antigen and get presented anyways.
Discuss in principle how T cell immunity could be measured in vitro.
The lab can do a variety of tests, whose principles should be quite obvious to us by now. Whole blood or white blood cells may be incubated with antigen in cell culture, and activation observed: one could look at cell numbers for proliferation, at cell size for activation (“blast transformation”), or at DNA synthesis using radiolabeled precursors. Cytokines released into the medium can be quantified. None of these is a routine test, however.
