IgM Augments Complement Bactericidal Activity with Serum from a Patient with a Novel CD79a Mutation

Antibody replacement therapy for patients with antibody deficiencies contains only IgG. As a result, concurrent IgM and IgA deficiency present in a large proportion of antibody deficient patients persists. Especially patients with IgM deficiency remain at risk for recurrent infections of the gastrointestinal and respiratory tract. The lack of IgM in the current IgG replacement therapy is likely to contribute to the persistence of these mucosal infections because this antibody class is especially important for complement activation on the mucosal surface. We evaluated whether supplementation with IgM increased serum bactericidal capacity in vitro. Serum was collected from a patient with agammaglobulinemia and supplemented with purified serum IgM to normal levels. Antibody and complement deposition on the bacterial surface was determined by multi-color flow cytometry. Bacterial survival in serum was determined by colony-forming unit counts. We present a patient previously diagnosed with agammaglobulinemia due to CD79A (Igα) deficiency revealing a novel pathogenic insertion variant in the CD79a gene (NM_001783.3:c.353_354insT). Despite IgG replacement therapy and antibiotic prophylaxis, this patient developed a Campylobacter jejuni spondylodiscitis of lumbar vertebrae L4–L5. We found that serum IgM significantly contributes to complement activation on the bacterial surface of C. jejuni. Furthermore, supplementation of serum IgM augmented serum bactericidal activity significantly. In conclusion, supplementation of intravenous IgG replacement therapy with IgM may potentially offer greater protection against bacterial infections, also in the context of increasing antibiotic resistance

Immunodeficiency in Bloom’s Syndrome

Bloom’s syndrome (BS) is an autosomal recessive disease, caused by mutations in the BLM gene. This gene codes for BLM protein, which is a helicase involved in DNA repair. DNA repair is especially important for the development and maturation of the T and B cells. Since BLM is involved in DNA repair, we aimed to study if BLM deficiency affects T and B cell development and especially somatic hypermutation (SHM) and class switch recombination (CSR) processes. Clinical data of six BS patients was collected, and immunoglobulin serum levels were measured at different time points. In addition, we performed immune phenotyping of the B and T cells and analyzed the SHM and CSR in detail by analyzing IGHA and IGHG transcripts using next-generation sequencing. The serum immunoglobulin levels were relatively low, and patients had an increased number of infections. The absolute number of T, B, and NK cells were low but still in the normal range. Remarkably, all BS patients studied had a high percentage (20–80%) of CD4+ and CD8+ effector memory T cells. The process of SHM seems normal; however, the Ig subclass distribution was not normal, since the BS patients had more IGHG1 and IGHG3 transcripts. In conclusion, BS patients have low number of lymphocytes, but the immunodeficiency seems relatively mild since they have no severe or opportunistic infections. Most changes in the B cell development were seen in the CSR process; however, further studies are necessary to elucidate the exact role of BLM in CSR

Clinical and virologic response to combination treatment with indinavir, zidovudine, and lamivudine in children with human immunodeficiency virus-1 infection: A multicenter study in The Netherlands.

Abstract OBJECTIVE: To evaluate the clinical, immunologic, and virologic response to indinavir, zidovudine, and lamivudine in children with human immunodeficiency virus-1 (HIV-1) infection. STUDY DESIGN: Twenty-eight HIV-1-infected children (3 months to 16 years of age) with or without prior treatment with reverse-transcriptase inhibitors and a HIV-1 RNA >5000 copies/mL and/or a CD4 cell count less than the lower limit of the age-specific reference value were treated with indinavir, zidovudine, and lamivudine. Pharmacokinetics of indinavir were determined in each child. RESULTS: The combination treatment was well tolerated in the majority of patients. Clinical improvement was seen in all patients. After 6 months of therapy, 70% of the patients had an HIV-1 RNA load below 500 copies/mL, whereas 48% of the children had a viral load below 40 copies/mL. Relative CD4 cell counts in relation to the lower limit of the age-specific reference value increased significantly from a median value of 79% at baseline to 106% after 6 months of therapy. The doses of indinavir necessary to achieve area under the curve values comparable to adult values varied from 1250 mg/m(2)/d to 2450 mg/m(2)/d. CONCLUSIONS: Highly active antiretroviral therapy consisting of indinavir, zidovudine, and lamivudine in children reduced HIV-1 RNA to less than 500 copies/mL in 70% of the children within 6 months. Improved CD4 cell counts were observed in most patients, as was a better clinical condition (no invasive or opportunistic infections, increased weight gain). Side effects of the triple therapy were mild. Highly active antiretroviral therapy can be used as successfully in children as in adults