Origin and evolutionary malleability of T cell receptor α diversity.

Lymphocytes of vertebrate adaptive immune systems acquired the capability to assemble, from split genes in the germline, billions of functional antigen receptors1-3. These receptors show specificity; unlike the broadly tuned receptors of the innate system, antibodies (Ig) expressed by B cells, for instance, can accurately distinguish between the two enantiomers of organic acids4, whereas T cell receptors (TCRs) reliably recognize single amino acid replacements in their peptide antigens5. In developing lymphocytes, antigen receptor genes are assembled from a comparatively small set of germline-encoded genetic elements in a process referred to as V(D)J recombination6,7. Potential self-reactivity of some antigen receptors arising from the quasi-random somatic diversification is suppressed by several robust control mechanisms8-12. For decades, scientists have puzzled over the evolutionary origin of somatically diversifying antigen receptors13-16. It has remained unclear how, at the inception of this mechanism, immunologically beneficial expanded receptor diversity was traded against the emerging risk of destructive self-recognition. Here we explore the hypothesis that in early vertebrates, sequence microhomologies marking the ends of recombining elements became the crucial targets of selection determining the outcome of non-homologous end joining-based repair of DNA double-strand breaks generated during RAG-mediated recombination. We find that, across the main clades of jawed vertebrates, TCRα repertoire diversity is best explained by species-specific extents of such sequence microhomologies. Thus, selection of germline sequence composition of rearranging elements emerges as a major factor determining the degree of diversity of somatically generated antigen receptors.

Human thymoma-associated mutation of the GTF2I transcription factor impairs thymic epithelial progenitor differentiation in mice.

Few human tumours present with a recurrent pathognomonic mutation in a transcription factor. Thymomas are an exception, with the majority of some subtypes exhibiting a distinct somatically acquired missense mutation in the general transcription factor GTF2I. Co-dominant expression of wild-type and mutated forms of Gtf2i in the mouse thymic epithelium is associated with aberrant thymic architecture and reduced thymopoietic activity. Phenotypic and molecular characterization of the mutant epithelium indicates that medullary differentiation is particularly affected as a result of impaired differentiation of bi-potent epithelial progenitors. The resulting gene expression signature is dominated by that of immature cortex-like thymic epithelial cells. TCR repertoire analysis of the cytopenic T cell compartment indicates efficient intrathymic selection; hence, despite marked homeostatic proliferation of T cell clones, autoimmunity is not observed. Thus, our transgenic mouse model recapitulates some aspects of the pathophysiology of a genetically defined type of human thymoma.

Antigen receptor repertoires of one of the smallest known vertebrates.

The rules underlying the structure of antigen receptor repertoires are not yet fully defined, despite their enormous importance for the understanding of adaptive immunity. With current technology, the large antigen receptor repertoires of mice and humans cannot be comprehensively studied. To circumvent the problems associated with incomplete sampling, we have studied the immunogenetic features of one of the smallest known vertebrates, the cyprinid fish Paedocypris sp. "Singkep" ("minifish"). Despite its small size, minifish has the key genetic facilities characterizing the principal vertebrate lymphocyte lineages. As described for mammals, the frequency distributions of immunoglobulin and T cell receptor clonotypes exhibit the features of fractal systems, demonstrating that self-similarity is a fundamental property of antigen receptor repertoires of vertebrates, irrespective of body size. Hence, minifish achieve immunocompetence via a few thousand lymphocytes organized in robust scale-free networks, thereby ensuring immune reactivity even when cells are lost or clone sizes fluctuate during immune responses.

Cytidine deaminase 2 is required for VLRB antibody gene assembly in lampreys.

The antibodies of jawless vertebrates consist of leucine-rich repeat arrays encoded by somatically assembled VLRB genes. It is unknown how the incomplete germline VLRB loci are converted into functional antibody genes during B lymphocyte development in lampreys. In Lampetra planeri larvae lacking the cytidine deaminase CDA2 gene, VLRB assembly fails, whereas the T lineage-associated VLRA and VLRC antigen receptor gene assemblies occur normally. Thus, CDA2 acts in a B cell lineage-specific fashion to support the somatic diversification of VLRB antibody genes. CDA2 is closely related to activation-induced cytidine deaminase (AID), which is essential for the elaboration of immunoglobulin gene repertoires in jawed vertebrates. Our results thus identify a convergent mechanism of antigen receptor gene assembly and diversification that independently evolved in the two sister branches of vertebrates.

[X-linked agammaglobulinemia in adults. Clinical evolution]. / Agammaglobulinemia ligada al cromosoma X en adultos. Evolución clínica.

X-linked agammaglobulinemia (XLA) is characterized by absent or severely reduced B cells, low or undetectable immunoglobulin levels and clinically by extracellular bacterial infections which mainly compromise the respiratory tract as well as recurrent diarrheas. The mainstay of treatment is gammaglobulin replacement therapy, which allows most patients to reach adulthood with high quality of life. We analyzed the clinical features of 14 patients over 18 years of age with XLA diagnosis that received treatment in our unit from the year 2003, the date the first patient was derived, until 2015. The average age at which patients were referred was 20.4 years old; age at the last consult was 25.5. The average follow-up time was 59.8 months. Previously to being diagnosed all patients had suffered infections, most frequently respiratory. After diagnosis all were started on intravenous gammaglobulin replacement treatment and in spite of infections being reduced in severity and frequency, there were cases of severe disease with long term sequelae. At the beginning of our follow-up 35.7% presented impaired respiratory function with only one case being severe. In no cases during this period did the respiratory function worsen, nor were there severe clinical complications. Three patients were switched to subcutaneous immunoglobulin treatment with good tolerance. The number of XLA cases is increasing, as most reach the second decade of life without serious complications and remain free of severe infectious disease and further impairment of their respiratory functions with the treatment.

Agammaglobulinemia ligada al cromosoma X en adultos: Evolucion clínica / X-linked agammaglobulinemia in adults. Clinical evolution

La agammaglobulinemia ligada al cromosoma X (XLA) se caracteriza por la ausencia o reducción significativa de linfocitos B, niveles bajos o indetectables de inmunoglobulinas y, clínicamente, por infecciones principalmente respiratorias por bacterias capsuladas extracelulares y diarrea recurrente. El tratamiento de reemplazo con gammaglobulina ha permitido a la mayor parte de los enfermos llegar a adultos con una buena calidad de vida. Analizamos las características clínicas de 14 pacientes mayores de 18 años con diagnóstico de XLA asistidos en nuestra Unidad desde 2003, fecha en que fue derivado el primer paciente, hasta 2015. La edad promedio en el momento de la derivación fue de 20.4 años, en el momento de la última consulta de 25.5. El tiempo promedio de seguimiento fue de 59.8 meses. Previo al diagnóstico todos habían presentado infecciones, las más frecuentes fueron las respiratorias. Posteriormente al diagnóstico todos iniciaron tratamiento de reemplazo con gammaglobulina endovenosa, y a pesar de que las infecciones disminuyeron en frecuencia y gravedad, en este período se presentaron enfermedades con secuelas graves. Al comenzar el seguimiento en nuestra Unidad, 35.7% presentaban deterioro de la función respiratoria, solo grave en un paciente. Durante el seguimiento ninguno presentó deterioro de la función respiratoria ni complicaciones clínicas importantes. Tres pasaron a gammaglobulina subcutánea con buena tolerancia. El número de adultos con XLA es cada vez mayor, la mayoría llegan a la segunda década de la vida sin complicaciones graves y bajo tratamiento se mantienen libres de enfermedades infecciosas graves y de progresión de sus secuelas pulmonares.

X-linked agammaglobulinemia (XLA) is characterized by absent or severely reduced B cells, low or undetectable immunoglobulin levels and clinically by extracellular bacterial infections which mainly compromise the respiratory tract as well as recurrent diarrheas. The mainstay of treatment is gammaglobulin replacement therapy, which allows most patients to reach adulthood with high quality of life. We analyzed the clinical features of 14 patients over 18 years of age with XLA diagnosis that received treatment in our unit from the year 2003, the date the first patient was derived, until 2015. The average age at which patients were referred was 20.4 years old; age at the last consult was 25.5. The average follow-up time was 59.8 months. Previously to being diagnosed all patients had suffered infections, most frequently respiratory. After diagnosis all were started on intravenous gammaglobulin replacement treatment and in spite of infections being reduced in severity and frequency, there were cases of severe disease with long term sequelae. At the beginning of our follow-up 35.7% presented impaired respiratory function with only one case being severe. In no cases during this period did the respiratory function worsen, nor were there severe clinical complications. Three patients were switched to subcutaneous immunoglobulin treatment with good tolerance. The number of XLA cases is increasing, as most reach the second decade of life without serious complications and remain free of severe infectious disease and further impairment of their respiratory functions with the treatment.