Student Reader

Immunological disorders

The most important function of the human immune system occurs at the cellular level of the blood and tissues. The lymphatic and blood circulation systems are highways for specialized white blood cells to travel around the body. White blood cells include B cells, T cells, natural killer cells, and macrophages. Each has a different responsibility, but all function together with the primary objective of recognizing, attacking and destroying bacteria, viruses, cancer cells, and all substances seen as foreign. Without this coordinated effort, a person would not be able to survive more than a few days, before succumbing to overwhelming infection.

Infections set off an alarm that alerts the immune system to bring out its defensive weapons. Natural killer cells and macrophages rush to the scene to gobble up and digest infected cells. If the first line of defense fails to control the threat, antibodies, produced by the B cells, upon the order of T helper cells, are custom-designed to hone in on the invader. Many disorders of the human immune system fall into two broad categories that are characterized by:

Attenuated ResponseThere are 'congenital' (inborn) and 'acquired' forms of immunodeficiency, characterized by an attenuated response. Chronic granulomatous disease, in which phagocytes have trouble destroying pathogens, is an example of the former, while AIDS ("Acquired Immune Deficiency Syndrome"), an infectious disease caused by the HIV virus that destroys CD4+ T cells, is an example of the latter. Immunosuppressive medication intentionally induces an immunodeficiency in order to prevent rejection of transplanted organs.
Overzealous ResponseOn the other end of the scale, an overactive immune system figures in a number of other disorders, particularly autoimmune disorders such as lupus erythematosus, type I diabetes (sometimes called "juvenile onset diabetes"), multiple sclerosis, psoriasis, and rheumatoid arthritis. In these, the immune system fails to properly distinguish between self and non-self, and attacks a part of the patient's own body. Other examples of overzealous immune responses in disease include hypersensitivities, such as allergies and asthma.

Problems in pathways

Isotype SwitchingT cell help through the CD40/CD40L interaction is required for isotype switching. The FLOW patterns show that expression of CD40 and CD40 L appears normal. Expression of AID is also required for isotype switching. If there is an I region present: The defect could be in CD40 or CD40L: an interaction between them is required to isotype switch. The defect could be an overproduction of IFN-γ which blocks DNA rearrangement (switching). The defect could not be in IL-4 or its receptor since there is transcription of the unrearranged gene. If there is no I region present: then it must be AID protein (if no transcripts are formed and no Ig is present).
T CellIf all you know is that T cells are not functioning -- or maybe not mounting a secondary response -- then a good defect candidate is CD40L.
No AntibodiesIf they are not rearranging, that is the likely cause of no expression. If they are rearranging, there is a defect in something required for surface expression: candidates are the membrane exon of the heavy chain, Ig-α, Ig-β, or surrogate light chain; or proteins required to transport the antibody to the surface.
No RearrangementFrequently caused by lack of RAG enzymes leading to no antibody production and no T cell maturation (arrested at DN stage).
CD40/CD40LNeeded for isotype switching.
IgG1/IgE deficiencyA selective decrease in IgG1 and IgE is observed. The most likely expanation is a defect in IL-4 (or IL-4R) or possibly an increase in IFN-γ because these selectively impact these isotypes. Since IgG2 and IgG3 remain essentially unchanged it does not appear to be a general defect such as CD40 or CD40L.
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