Immunoglobulins, MHC and T Cell receptors genes in Cetaceans

Cetaceans correspond to mammals that have returned to the marine environment. Adaptive changes are very significant with the conversion of the limbs into flippers. It is studied the changes that have occurred in immunoglobulins, MHC class I and II and T cell receptors genes. Constant regions of immunoglobulins are similar to those of the rest of mammals. An exception is the IgD gene, which is composed of three CH domains but CH1 similar to CH1 of immunoglobulin M. In the IGHV locus, it exist a decrease in the number of VH genes with the absence of genes within Clan I. The number of Vλ genes is greater than that of Vκ. In the genes for T lymphocyte receptors, it exists a decrease in the number of Vα genes with loss of significant clades and subclades. In Vβ and Vγ, there is also the loss of clades. These declines of Vα, Vβ and Vγ are not present Artiodactyla, and they are specific to Cetaceans. In MHC present tree evolutive lines of class I genes. These species have DQ, DR, DO and DM genes, but they are no present DP genes.

LRPAP1 Is a Frequent B-Cell Receptor Antigen in Mantle Cell Lymphoma (MCL)

Introduction: Chronic antigenic stimulation may play an important role in the pathogenesis of malignant lymphomas. Although most MCL cases are believed to have an antigen-naive B cell as cell of origin, overrepresentation of certain VH genes has been reported. Therefore we screened BCRs from MCLs for possible antigens. Methods: BCRs were expressed as recombinant Fabs based on corresponding pairs of functional variable region heavy and light chain genes, which had been amplified from isolated genomic DNA of snap-frozen MCL specimens and established MCL cell lines. The purified BCR-Fabs were checked for binding to proteins expressed on macroarrays of human cDNA expression libraries and on bacterial lysates. In addition, sera from patients with MCL were screened for antibodies against respective BCR antigens. Results: The recombinant MCL-BCR derived Fabs from 9 patients and of four established MCL cell lines were tested on protein arrays. Recombinant lymphoma-BCR-derived Fabs from 4/9 patients and from 1/4 MCL cell lines reacted with human low density lipoprotein receptor-related protein associated protein 1 (LRPAP1). Specific secondary modifications of LRPAP1 explaining its autoimmunogenicity were not found. 8/30 patients with MCL had anti-LRPAP1-antibodies in their serum, which was the case in only 1/200 healthy controls. Finally, LRPAP1 specifically induced proliferation of Maver1 cells that express a BCR with specificity for LRPAP1. Conclusions: LRPAP1 is the first molecularly defined antigenic target of MCL-BCRs. The high frequency of LRPAP1-reactive BCRs in MCL suggests a role of LRPAP1 in the pathogenesis of MCL, even in cases with unmutated VH genes. The prevalence of LRPAP1-antibodies in MCL patients and healthy controls identifies LRPAP1-antibody as the first serologic risk factor for MCL (odds ratio: 72.36) Supported by Wilhelm-Sander-Stiftung Disclosures No relevant conflicts of interest to declare.

Restricted, canonical, stereotyped and convergent immunoglobulin responses

It is becoming evident that B-cell responses to particular epitopes or in particular contexts can be highly convergent at the molecular level. That is, depending on the epitope targeted, persons of diverse genetic backgrounds and immunological histories can use highly similar, stereotyped B-cell receptors (BCRs) for a particular response. In some cases, multiple people with immunity to a particular epitope or with a type of B-cell neoplasia will elicit antibodies encoded by essentially identical immunoglobulin gene rearrangements. In other cases, particular VH genes encode antibodies important for immunity against pathogens such as influenza and HIV. It appears that the conserved antibody structures driving these stereotyped responses are highly limited and selected. There are interesting and important convergences in the types of stereotyped BCRs induced in conditions of immunity and B-cell-related pathology such as cancer and autoimmunity. By characterizing and understanding stereotyped B-cell responses, novel approaches to B-cell immunity and in understanding the underlying causes of B-cell pathology may be discovered. In this paper, we will review stereotyped BCR responses in various contexts of B-cell immunity and pathology.

FoxO1 induces Ikaros splicing to promote immunoglobulin gene recombination

Somatic rearrangement of immunoglobulin (Ig) genes is a key step during B cell development. Using pro–B cells lacking the phosphatase Pten (phosphatase and tensin homolog), which negatively regulates phosphoinositide-3-kinase (PI3K) signaling, we show that PI3K signaling inhibits Ig gene rearrangement by suppressing the expression of the transcription factor Ikaros. Further analysis revealed that the transcription factor FoxO1 is crucial for Ikaros expression and that PI3K-mediated down-regulation of FoxO1 suppresses Ikaros expression. Interestingly, FoxO1 did not influence Ikaros transcription; instead, FoxO1 is essential for proper Ikaros mRNA splicing, as FoxO1-deficient cells contain aberrantly processed Ikaros transcripts. Moreover, FoxO1-induced Ikaros expression was sufficient only for proximal VH to DJH gene rearrangement. Simultaneous expression of the transcription factor Pax5 was needed for the activation of distal VH genes; however, Pax5 did not induce any Ig gene rearrangement in the absence of Ikaros. Together, our results suggest that ordered Ig gene rearrangement is regulated by distinct activities of Ikaros, which mediates proximal VH to DJH gene rearrangement downstream of FoxO1 and cooperates with Pax5 to activate the rearrangement of distal VH genes.