Educational paper: Syndromic forms of primary immunodeficiency

The syndromic primary immunodeficiencies are disorders in which not only the immune system but also other organ systems are affected. Other features most commonly involve the ectodermal, skeletal, nervous, and gastrointestinal systems. Key in identifying syndromic immunodeficiencies is the awareness that increased susceptibility to infections or immune dysregulation in a patient known to have other symptoms or special features may hint at an underlying genetic syndrome. Because the extraimmune clinical features can be highly variable, it is more difficult establishing the correct diagnosis. Nevertheless, correct diagnosis at an early age is important because of the possible treatment options. Therefore, diagnostic work-up is best performed in a center with extensive expertise in this field, having immunologists and clinical geneticists, as well as adequate support from a specialized laboratory at hand. This paper provides the general pediatrician with the main clinical features that are crucial for the recognition of these syndromes

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

The Same IκBα Mutation in Two Related Individuals Leads to Completely Different Clinical Syndromes

Both innate and adaptive immune responses are dependent on activation of nuclear factor κB (NF-κB), induced upon binding of pathogen-associated molecular patterns to Toll-like receptors (TLRs). In murine models, defects in NF-κB pathway are often lethal and viable knockout mice have severe immune defects. Similarly, defects in the human NF-κB pathway described to date lead to severe clinical disease. Here, we describe a patient with a hyper immunoglobulin M–like immunodeficiency syndrome and ectodermal dysplasia. Monocytes did not produce interleukin 12p40 upon stimulation with various TLR stimuli and nuclear translocation of NF-κB was impaired. T cell receptor–mediated proliferation was also impaired. A heterozygous mutation was found at serine 32 in IκBα. Interestingly, his father has the same mutation but displays complex mosaicism. He does not display features of ectodermal dysplasia and did not suffer from serious infections with the exception of a relapsing Salmonella typhimurium infection. His monocyte function was impaired, whereas T cell function was relatively normal. Consistent with this, his T cells almost exclusively displayed the wild-type allele, whereas both alleles were present in his monocytes. We propose that the T and B cell compartment of the mosaic father arose as a result of selection of wild-type cells and that this underlies the widely different clinical phenotype

Kattarklórskvilli

Neðst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn View/OpenKvilli sem kenndur er við kattarklór (cat scratch disease) greindist fyrst árið 1935. Það var hins vegar ekki fyrr en fimmtán árum síðar, árið 1950 að fyrsta greinin birtist í læknisfræðitímariti (1). Síðan hafa meira en 1000 greinar frá flestum heimshornum verið birtar varðandi kattarklórskvilla. Á Íslandi, sem annars staðar, hefur nokkrum sinnum vaknað spurning hvort sjúklingur með eitlabólgu hafi kattarklórskvilla. Ekki er að fullu ljóst hvort sjúkdómurinn hafi nokkru sinni greinst með vissu á Íslandi. Þó má ætla að kattarklórskvilli komi fyrir á landinu eins og annars staðar í heiminum. Til samanburðar má geta þess að álitið er að kvillinn greinist með vissu í 2000 einstaklingum ár hvert í Bandaríkjunum. Nýgengi sjúkdómsins er áreiðanlega miklu meira. Þótt kattarklórskvilli sé venjulega ekki alvarlegur eða hættulegur sjúkdómur er greining kvillans mikilvæg og hann ber að hafa í huga meðal annars við mismunagreiningu á eitlabólgum, gleypifrumuhnúðum (granulomas) og óvenjulegum sýkingum

Kattarklórskvilli

Neðst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn View/OpenKvilli sem kenndur er við kattarklór (cat scratch disease) greindist fyrst árið 1935. Það var hins vegar ekki fyrr en fimmtán árum síðar, árið 1950 að fyrsta greinin birtist í læknisfræðitímariti (1). Síðan hafa meira en 1000 greinar frá flestum heimshornum verið birtar varðandi kattarklórskvilla. Á Íslandi, sem annars staðar, hefur nokkrum sinnum vaknað spurning hvort sjúklingur með eitlabólgu hafi kattarklórskvilla. Ekki er að fullu ljóst hvort sjúkdómurinn hafi nokkru sinni greinst með vissu á Íslandi. Þó má ætla að kattarklórskvilli komi fyrir á landinu eins og annars staðar í heiminum. Til samanburðar má geta þess að álitið er að kvillinn greinist með vissu í 2000 einstaklingum ár hvert í Bandaríkjunum. Nýgengi sjúkdómsins er áreiðanlega miklu meira. Þótt kattarklórskvilli sé venjulega ekki alvarlegur eða hættulegur sjúkdómur er greining kvillans mikilvæg og hann ber að hafa í huga meðal annars við mismunagreiningu á eitlabólgum, gleypifrumuhnúðum (granulomas) og óvenjulegum sýkingum