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Front Immunol ; 9: 2984, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30619340


B cell activation via the B cell receptor (BCR) signalosome involves participation of signaling molecules such as BTK and BLNK. Genetic defects in these molecules are known to impair B cell differentiation and subsequently lead to agammaglobulinemia. Here we identified novel mutations in BTK and BLNK in two unrelated patients that perturb the intrinsic B-cell receptor signaling pathway and lead to selective IgM deficiency, whereas production of other immunoglobulin isotypes and IgG antibody response remain intact. Currently it is unknown how BCR signaling strength affects mature B cell development in humans. Both patients show reduced levels of BCR signalosome phosphorylation as well as impaired BCR-dependent Ca2+ influx, which was accompanied by a marked decrease in IgD+IgM+CD27+ MZ-like B-cells. We further describe reduced expression of essential B cell differentiation factors such as BAFF-R and T-Bet in the patients' B-cells, which might contribute to the observed deficiency of MZ-like B cells. MZ-like B cells are known to produce natural IgM antibodies that play an essential role in immune homeostasis. By using surface plasmon resonance (SPR) technology and a synthetic blood group A trisaccharide as antigen we were able to show that both patients lack the presence of anti-blood group A IgM considered to be prototypical natural antibodies whereas IgG levels were normal. Antibody binding dynamics and binding affinity of anti-blood group A IgG were comparable between patients and healthy controls. These results indicate that human IgM deficiency can be associated with signaling defects in the BCR signalosome, defective production of natural IgM antibodies in the blood group A/B/0 system and abnormalities in B cell development.

Proteínas Adaptadoras de Transdução de Sinal/genética , Tirosina Quinase da Agamaglobulinemia/genética , Agamaglobulinemia/genética , Linfócitos B/imunologia , Imunoglobulina M/deficiência , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adolescente , Adulto , Tirosina Quinase da Agamaglobulinemia/metabolismo , Agamaglobulinemia/imunologia , Linfócitos B/metabolismo , Humanos , Imunoglobulina M/imunologia , Masculino , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia
Clin Immunol ; 183: 41-45, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28705765


Over the past decades, a pleiotropic spectrum of B-cell intrinsic defects leading to early onset agammaglobulinemia and absent B cells has been described. Herein we report terminal 14q32.33 deletion as a novel cause of agammaglobulinemia. We describe a 20-year old man with a 1MB terminal 14q32.33 deletion resulting in a loss of the entire Immunoglobulin heavy chain gene region of chromosome 14. The patient presented with absent serum immunoglobulin levels and absent circulating B cells since age 2. The clinical picture was dominated by severe episodes of recurrent upper respiratory tract infections. In the literature, the most prevalent features of terminal 14q32.33 deletions include mental disability, facial malformation, hypotonia, seizures, and visual problems with retinal abnormalities. Neither increased susceptibility to infections nor agammaglobulinemia have been described as a manifestation of terminal 14q32.33 deletion. Thus, our findings expand the known clinical spectrum of terminal 14q32.33 deletion to include susceptibility to infections.

Agamaglobulinemia/genética , Deleção Cromossômica , Cromossomos Humanos Par 14/genética , Agamaglobulinemia/imunologia , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Masculino , Adulto Jovem
PLoS One ; 10(7): e0133220, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26186701


Loss of function mutations in the recombination activating genes RAG1 and RAG2 have been reported to cause a T-B-NK+ type of severe combined immunodeficiency. In addition identification of hypomorphic mutations in RAG1 and RAG2 has led to an expansion of the spectrum of disease to include Omenn syndrome, early onset autoimmunity, granuloma, chronic cytomegalovirus- or EBV-infection with expansion of gamma/delta T-cells, idiophatic CD4 lymphopenia and a phenotype resembling common variable immunodeficiency. Herein we describe a novel presentation of leaky RAG1 and RAG2 deficiency in two unrelated adult patients with impaired antibody production against bacterial polysaccharide antigens. Clinical manifestation included recurrent pneumonia, sinusitis, otitis media and in one patient recurrent cutaneous vasculitis. Both patients harbored a combination of a null mutation on one allele with a novel hypomorphic RAG1/2 mutation on the other allele. One of these novel mutations affected the start codon of RAG1 and resulted in an aberrant gene and protein expression. The second novel RAG2 mutation leads to a truncated RAG2 protein, lacking the C-terminus with intact core RAG2 and reduced VDJ recombination capacity as previously described in a mouse model. Both patients presented with severely decreased numbers of naïve CD4+ T cells and defective T independent IgG responses to bacterial polysaccharide antigens, while T cell-dependent IgG antibody formation e.g. after tetanus or TBEV vaccination was intact. In conclusion, hypomorphic mutations in genes responsible for SCID should be considered in adults with predominantly antibody deficiency.

Proteínas de Ligação a DNA/genética , Proteínas de Homeodomínio/genética , Síndromes de Imunodeficiência/genética , Mutação , Proteínas Nucleares/genética , Adulto , Linfócitos T CD4-Positivos/imunologia , Proteínas de Ligação a DNA/metabolismo , Feminino , Proteínas de Homeodomínio/metabolismo , Humanos , Síndromes de Imunodeficiência/diagnóstico , Lipopolissacarídeos/imunologia , Proteínas Nucleares/metabolismo