This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The major goals of the project entitled 'Biologic Definition of Host Defenses in Man' are to define the defects in lymphocyte differentiation or function associated with immune deficiency diseases, lymphoid malignancies, and disorders of immunoregulation. The underlying thesis is that some of the remaining gaps in knowledge about the human immune system can be addressed by comparative analysis of the normal ontogeny of the immune system, and through the analysis of immune system defects in primary immunodeficiency diseases. Emphasis is on (1) investigation of differentiation and maturation of lymphoid cells and the factors governing their normal development, (2) determination of the site, pathogenetic mechanism, and genetics of aberrant cellular differentiation and its role in the etiology of inherited or acquired immunodeficiency, and (3) characterization of quantitative and functional alterations or the subpopulations of immunocompetent cells in disease states. This protocol functions as the means for seven NIH-supported investigators (Table 1) to extend their studies, most of which are focused on model systems such as mice, into the human arena.Genetic susceptibility to selective IgA deficiency (IgAD) and common variable immunodeficiency (CVID) are the most common forms of primary humoral immune deficiency in the United States. IgAD is recognized in approximately 1 in 50,000. Patients with these diagnoses fit within a spectrum of immune deficiency that begins with IgAD, progresses through IgAD with IgG subclass deficits, and culminates in the panhypogammaglobulinemia of frank CVID. In previous studies under this protocol, we established that approximately 80% of patients with the extended diagnosis of IgAD/CVID in our study population had inherited part or all of two extended MHC haplotypes; HLA -A1-B8-DR17(3)-DQ2 and HLA -B44-DR7-DQ2; both of which are significantly more common in Americans of European descent than those of African or Asian descent.In the course of screening patients for our study, we identified a large number of non-smoking young and middle-aged adults with recurrent sinopulmonary infections (ReSPI) who did not have major serum immunoglobulin deficits and had no other recognizable host defense deficit to explain their enhanced susceptibility to infection. Included in this population are first or second degree relatives of our IgAD/CVID patients who have normal serum IgM, IgG, and IgA levels; yet suffer with almost the same intensity of infection as their frankly immune deficient relatives. Over the past year, we completed our initial test of the hypothesis that the inheritance of one or more of the susceptibility MHC alleles might be associated with recurrent URI even in the presence of adequate serum immunoglobulin levels.Among our study population, we identified 62 consecutive study subjects who presented with a history of unexplained recurrent sinopulmonary infections (ReSPI) and compared their clinical history and MHC haplotypes to those exhibited by 61 patients with CVID. The average IgM level was 124+9 mg/dl (nl 50-450), IgG 915+31 mg/dl (nl 600-1500), and IgA 198+13 mg/dl (nl 60-380). The average age at the time of onset of sinusitis (55 patients) was 21+2 in the RSPI patients as compared to the 17+2 in 46 patients with CVID. Average age at the onset of bronchitis (38 patients) was 18+3 versus 18+2 in 46 with CVID. Average at the onset of pneumonia (35 patients) was 22+3 versus 25+3 in 37 with CVID. Together, 74% of the 62 patients had inherited all or a portion of the two IgAD/CVID susceptibility haplotypes as compared to 85% of the 61 CVID patients. When compared to MHC prevalence in 1627 Caucasian bone marrow donors, the prevalence of the RSPI group differed significantly for HLA B44 (44% versus 14%, p <0.001, relative risk 3.0). The prevalence of HLA B8, DR17(3), and DR7 differed significantly when compared to published antigen frequencies of US Caucasians (P <0.001). This work is in press in Clinical Immunology (1).Our data suggest that the spectrum of IgAD/CVID associated with the two MHC haplotypes noted above, and especially HLA -B44, may extend to include patients whose serum immunoglobulins are normal, but who still exhibit increased susceptibility to sinopulmonary infection. Given the prevalence of HLA -B44 in the general population, it is our hypothesis that inheritance of this allele may represent one of the most significant risk factors for the development of recurrent respiratory infections in our population.Given the split in association between the locus near HLA class II and class I in terms of susceptibility to RESPI, we sought to assess whether the phenotype exhibited by CVID patients who had inherited HLA associated class I susceptibility alleles might differed differ from those who had not. We obtained a FACS analysis of B cell numbers in 55 consecutive CVID patients whose MHC haplotype had been determined. We found that patients who had not inherited the class I alleles *B44 or *B8 had significantly lower total B cell numbers than patients with *B44 or *B88, whereas differences in B cell numbers were not observed between patients that had inherited the class II alleles *DR3(17) or *DR7, and those that had not. These data provide further support for the hypothesis that there are separate alleles for immune deficiency in the locus associated with class I and the locus associated with class II; and that these loci exhibit different mechanisms of action in promoting susceptibility to immune deficiency. A manuscript reporting these findings is in preparation and will be submitted within the next month.
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