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  Chapter 49 Primary Immunodeficiency Diseases
       Rebecca H. Buckley
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Immunodeficiency with Elevated IgM (Hyper IgM)

The hyper IgM syndrome is characterized by very low serum IgG, IgA, and IgE levels but either a normal or a markedly elevated concentration of polyclonal IgM. It is now known that the hyper IgM syndrome includes at least four distinct genetic diseases. Patients with this rare primary immunodeficiency syndrome resemble those with agammaglobulinemia in their susceptibility to encapsulated bacterial infections (48-50). However, patients with one of the X-linked forms of hyper IgM also frequently present in infancy with Pneumocystis carinii pneumonia. The finding that many also have coexistent neutropenia was formerly considered a possible explanation for the susceptibility of some such patients to opportunistic infection; however, it is now known that one X-linked disease resulting in this syndrome is actually a T-cell defect, more likely accounting for that susceptibility. Thus far, two X-linked and two autosomal recessive diseases have been found to cause this syndrome, and there are likely to be more. Distinctive clinical features permit presumptive recognition of the type of mutation in these patients, thereby aiding proper choice of therapy. However, all such patients should undergo molecular analysis to ascertain the affected gene for purposes of genetic counseling, carrier detection, and definitive therapy.

CD154 (CD40 Ligand) Deficiency

Like boys with XLA, those with XHIM syndrome may become symptomatic during the first or second year of life with recurrent pyogenic infections. However, they also are highly prone to have Pneumocystis carinii pneumonia and to have profound neutropenia (4,48,49). They have very small tonsils and a paucity of palpable lymph nodes. Normal numbers of B lymphocytes are usually present in the circulation of these patients.

Until the early 1990s, this condition was classified as a B-cell defect because only IgM is produced. However, in 1986, B cells from patients with XHIM syndrome were shown to have the capacity to synthesize IgM, IgA, and IgG normally when these cells were cocultured with a "switch" T-cell line, a finding suggesting that in those patients the defect lay in T-lineage cells (51). This was puzzling, because routine tests of T-cell function were usually normal in such patients. In 1993, the abnormal gene in XHIM syndrome was localized to Xq26 (52) and was identified by five groups almost simultaneously (53-56). The gene product is a surface molecule known as CD154 (or CD40 ligand) on the surfaces of activated helper T cells (57) that interacts with CD40 molecules on B cells(53). Cross-linking of CD40 on either normal or XHIM B cells with a monoclonal antibody to CD40 or with soluble CD154 in the presence of cytokines (IL-2, IL-4, or IL-10) causes the B cells (which are intrinsically normal in XHIM syndrome) to undergo proliferation and isotype switching and to secrete various types of immunoglobulins. CD154 is a type II integral membrane glycoprotein with significant sequence homology to tumor necrosis factor (TNF); it is found only on activated T cells, primarily of the CD4 phenotype (Fig. 2) (57). Mutations in the gene encoding CD154 on XHIM patientsí T cells result in a lack of signaling of their normal B cells when their T cells are activated. Therefore, XHIM B cells fail to undergo isotype switching and produce only IgM; there is an absence of CD27+ memory B cells (58). Lymph node histology shows only abortive germinal center formation and a severe depletion and phenotypic abnormalities of follicular dendritic cells (59). Of further importance to effective immune responses, the lack of stimulation of CD40 also causes these patientsí B cells not to up-regulate CD80 and CD86. The latter are important co-stimulatory molecules that interact with CD28/cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) on T cells (60). The failure of interaction of the molecules of those pathways results in a propensity for tolerogenic T-cell signaling and defective recognition of tumor cells.

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FIG. 2. Cartoon showing the role of the CD40 ligand (CD154) in B-cell class switching. The CD154 gene is mutated in X-linked hyper lgM. Thus, this is a T-cell, not a B-cell, defect. From Allen RC, Armitage RJ, Conley ME, et al. (53), with permission.

More than 73 distinct point mutations or deletions in the gene encoding CD154 have been identified in 87 unrelated XHIM families, giving rise to frameshifts, premature stop codons, and single amino acid substitutions, most of which were clustered in the TNF homology domain located in the carboxy-terminal region (50). A highly polymorphic microsatellite dinucleotide (CA) repeat region in the 3´ untranslated end of the gene for CD154 is useful for detecting carriers of XHIM and for making a prenatal diagnosis of this condition (61).

In a retrospective study of 56 patients with XHIM syndrome, 13 (23.3%) had died, and the mean age at death was 11.7 years (49). In addition to opportunistic infections such as Pneumocystis carinii pneumonia, there is an increased incidence of cryptosporidial enteritis and subsequent liver disease in this syndrome. There is also an increased risk of malignancy. Because of the poor prognosis, the treatment of choice is a human leukocyte antigen (HLA)-identical sibling bone marrow transplant at an early age (62,63). Treatment for this condition also includes monthly IVIG infusions (64). In some patients with severe neutropenia, the use of granulocyte colony-stimulating factor has been beneficial (65).

Nuclear Factor kB Essential Modulator (NEMO or Ikkg) Deficiency

This is a newly recognized syndrome characterized most often clinically as anhidrotic ectodermal dysplasia with associated immunodeficiency (EDA-ID) in males and incontinentia pigmenti in females (66,67). The condition results from mutations in the IKBKG gene at position 28q on the X chromosome that encodes NEMO. NEMO is a regulatory protein that serves as a scaffold for two kinases necessary for activation of the transcription factor NFkB. Activation of NFkB by proinflammatory stimuli normally leads to increased expression of genes involved in inflammation, such as TNF-a and IL-12. B cells from patients with NEMO deficiency fail to undergo class switch recombination, and their antigen-presenting cells fail to produce TNF-a and IL-12 (67). Germline loss-of-function mutations cause the X-linked dominant condition incontinentia pigmenti and are lethal in male fetuses. Mutations in the coding region of IKBKG are associated with EDA-ID.

The immunodeficiency has been variable; most patients with EDA-ID have shown impaired antibody responses to polysaccharide antigens (66). However, two patients with EDA-ID presented with hyper IgM syndrome (67). Pharmacologic inhibitors of NFkB activation have been shown to down-regulate CD154 mRNA and protein levels, a finding suggesting the mechanism of hyper IgM in this condition (68). Stop codon mutations in IKBKG are associated with osteopetrosis, lymphedema, EDA, and immunodeficiency (OL-EDA-ID). Neither type of mutation abolishes NFkB signaling entirely. The immune cells of patients with OL-EDA-ID respond poorly to lipopolysaccharide, IL-1b, IL-18, TNF-a, and CD154, a finding accounting for the seriousness of their infections. Patients with hyper IgM syndrome who have this defect should be easily recognizable because of the presence of EDA.

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