Although the MHC genes reside on chromosome 6, a host of serious immunodeficiency disorders have been linked with mutations or deletions of genes on the X-chromosome. The X-chromosome is probably one of the most important from an immunological point of view. Naturally, all such disorders express themselves phenotypically in boys. As there is no normal allele to balance out these defects in males, the resulting immunodeficiency is severe, and manifests early in life.
Bruton described a X-linked syndrome with complete absence of immunoglobulins called X-linked agammaglobulinaemia (XLA). The disease is also named after him. The condition is because of a defect in a cellular tyrosine kinase, called btk, that halts the development of B-cells. Female carriers can be discerned due to the phenomenon of X-inactivation, described elsewhere on this blog. Thus, all circulating B cells will have been selected out by virtue of having inactivated the defective X-chromosome. OTOH, cells that do not depend on the defective gene for their function, such as T-cells, will have random inactivation of either X-chromosome, with a 1:1 ratio of such cells in circulation.
The earliest antibody isotype to be made by B-cells is IgM. Later, as the B-cell matures, en route to its ultimate role as the plasma cell, there is switching of the isotype to production of other antibodies, namely IgG, IgA or IgE. Along with this process of isotype switching, random mutations are introduced in the variable region of the immunoglobulin molecule, a process that is called somatic hypermutation. This process increases the affinity with which the B-cell receptor and its secreted immunoglobulin bind their putative antigen, a phenomenon called affinity maturation. The latter occurs only when the B-cell is exposed to its specific antigen in peripheral lymphoid tissues. This whole process cannot occur without the aid of helper T-cells, which are also constantly traversing peripheral lymphoid tissues, having entered through small blood vessels called high endothelial venules. The fact that an antigen specific B cell meets an antigen specific T cell is something of a small miracle- the odds of this happening has been calculated as being of the order of 10^-10. But meet they do, in the Tcell/Bcell border zones of lymph nodes and the spleen. T cells have on their surface a molecule called CD40 ligand (also called CD154). This ligates CD40 on B cells, providing a co-stimulatory signal that allows isotype switching and somatic hypermutaion to occur. It follows therefore, that in the absence of CD40-CD40L interaction, isotype switching will not occur, and the B-cells will continue to express one antibody isotype- IgM. This is exactly what happens in X-linked hyper-IgM syndrome, where there is a defect in the CD40 ligand on T cells. The interaction is bidirectional, and also activates T cells to express other co-stimulatory molecules. Thus, there is also a T-cell defect in this condition.
Other causes of hyper IgM syndrome have been identified. Predictably, defects in CD40 will give rise to a similar condition. A condition called NEMO syndrome leads to the same phenotype, as does deficiency of an enzyme called activation induced cytidine deaminase or AID, which is essential for the process of both isotype switching and somatic hypermutation. This latter only affects B-cells and thus causes a milder immunodeficiency than the first three aetiologies.
A further, much more severe immunodeficiency disorder has been characterised as "Severe Combined Immunodeficiency" or SCID. SCID has either X linked or autosomal recessive forms of inhertance. The X-linked form, which accounts for around 60% of cases, is due to deficiency of the gamma chain of the receptor of Interleukin-2 (IL-2). IL-2 is the most important survival and growth factor for T cells and is induced by co-stimulation of T cells through CD28 by B7 present on APCs, a process that's been described elsewhere on this blog. Upon activation, 3 transcription fators- nFkappaB, AP-1 and NFAT, are induced in the T cell, which leads to a hundred-fold surge in the production of IL-2. IL-2 is an autocrine cytokine- it acts on the T cell itself, through the IL-2 receptor. This receptor is trimeric when fully functional, and has alpha, beta and gamma chains. The beta and gamma chains exist as a dimer in the naive T cell. When the T cell is activated by its antigen and through co-stimulation, the beta-gamma heterodimer associates with the alpha chain, thus making a fully functional receptor, with a very high affinity for IL-2. This cannot happen in the absence of the gamma chain, which is defective in most cases of X-SCID. Other causes of X-SCID have been described including the absence of Janus Kinase-3 (JAK-3) and a defect in the gene that is responsible for the IL-7 receptor. In addition, autosomal forms of this condition exist due to deficiency of RAG-1 and RAG-2 recombinase enzymes which catalyse the somatic rearrangement of DNA in T and B cells that determine receptor specificity, a rare syndrome called ARTEMIS and deficiency of an enzyme called adenosine deaminase.
In addition to all these X-linked immunodeficiency disorders, an autoimmune X-linked condition has also been described. This is called IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, and X-linkage). This condition is caused by a mutation in the gene for FoxP3, an essential transcription factor for natural Treg(CD4 CD25)cells, and results in severe allergic inflammation, autoimmune polyendocrinopathy, diarrhoea, haemolytic anaemia and thrombocytopaenia.
Since all the above conditions are recessive, female carriers of defective genes are phenotypically normal and do not manifest immunodeficiency.
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