Baff (cytokine)

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Baff (cytokine)
Properties of human protein
Mass / length primary structure 285 amino acids
Secondary to quaternary structure Membrane protein
Identifier
Gene name TNFSF13B
External IDs
Occurrence
Parent taxon Mammals

BAFF ( B cell activating factor ) is a cytokine of the TNF superfamily and is essential for the activation, differentiation and survival of B cells , which is mainly produced by neutrophils , monocytes , macrophages and dendritic cells in mammals . Synonyms are TNFSF13B ( tumor necrosis factor superfamily member 13B - accordingly, BAFF is coded on the TNFSF13B gene), BLyS ( B lymphocyte stimulator ), TALL-1, zTNF4 or CD257 antigen ( cluster of differentiation 257). It is a 285 amino acid long glycoprotein with a glycosylation at position 124 and is a type 2 transmembrane protein .

There is an isoform that lacks the membrane anchor and is therefore freely mobile in the cytosol. It is created through post-translational modification and contains 152 amino acids.

Knockout mice that are Baff deficient show impaired B-cell development in which development in the transitional (T1) stage is blocked. These mice have hardly any mature follicular B cells and hardly any marginal zone B cells. The few mature B cells that do appear do not express the surface markers CD21 and CD23 . B1 cells, on the other hand, develop normally in the Baff-deficient animals; the early cells of the B-lymphoid lineage in the bone marrow are also not affected.

In contrast, mice with overexpression of BAFF have an autoimmune disease that is similar to human systemic lupus erythematosus and Sjogren's syndrome .

Receptors

There are three receptors for BAFF and its alternative ligand APRIL ( a proliferation-inducing ligand , CD256 antigen):

  • BAFF receptor (BAFF-R) on the B cells binds the trimeric BAFF , which is soluble in plasma
  • BCMA ( B-cell maturation antigen ) on the plasma cells , mainly binds trimeric APRIL, and trimeric BAFF only weakly.
  • TACI ( transmembrane activator and calcium modulator and cyclophilin-ligand activator ) is found on B cells and there especially on B1 cells, which act in a similar way to the innate immune response system ( innate-like B1 cells ), but only binds higher grade oligomers from BAFF or APRIL.

Medical importance

In general, BAFF and APRIL promote the proliferation and differentiation of B cells, but the effect via the TACI receptor is much more complex and not yet fully understood. TACI-deficient mice also show increased B-cell proliferation, but also increased autoimmune diseases . For example, a clinical study on multiple sclerosis with a BAFF / APRIL inhibitor (atacicept) had to be terminated in advance, as twice as many relapses occurred in the treatment group as in the placebo group. In any case, BAFF also mediates an inhibitory, pro- apoptotic effect on B cells via the TACI receptor .

The monoclonal anti-BAFF human antibody belimumab has been approved in Europe for the treatment of systemic lupus erythematosus (SLE) since 2011 .

There is an isoform that lacks the membrane anchor and is therefore freely mobile in the cytosol. It is created through post-translational modification and contains 152 amino acids.

variant

In Sardinia , an island with one of the world's highest rates of multiple sclerosis (MS) and systemic lupus erythematosus (SLE), a genome-wide association study described a BAFF variant that significantly increases the risk of both diseases, but at the same time has undergone a selection because it protected against malaria , which was endemic until the 1950s . For MS, the odds ratio OR = 1.27. In an embedded case-control study , the risk of SLE with an OR = 1.38 in Sardinia was also found to be significantly higher.

This variant, referred to as "BAFF-var" is an insertion - deletion , which is through the exchange of five nucleotides by an adenine to an alternative polyadenylation of the exon following 6 3'UTR ( 3 'untranslated region ) is (more precisely: AAT [GCTGT / A] AA). Since this variant has a higher resistance to binding to the cell's own microRNA and thus escapes the micro-RNA-controlled premature degradation, higher concentrations of "BAFF-var" are found.

This "BAFF-var" shows a high frequency of 26.5% in Sardinia, and the further away it is, the rarer it is. In Italy it is still found in 5.7%, in Spain in 4.9% and in Great Britain and Sweden only in 1.8% each.

swell

  • Fabienne Mackay, William A. Figgett, Damien Saulep, Melanie Lepage, Margaret L. Hibbs: B-cell stage and context-dependent requirements for survival signals from BAFF and the B-cell receptor . In: Immunological Reviews . tape 237 , no. 1 , 2010, p. 205–225 , doi : 10.1111 / j.1600-065X.2010.00944.x (English).

Individual evidence

  1. ↑ Orthologist at OMA
  2. ↑ Barbara Schiemann, Jennifer L. Gommerman, Kalpit Vora, Teresa G. Cachero, Svetlana Shulga-Morskaya, Max Dobles, Erica Frew, Martin L. Scott: An Essential Role for BAFF in the Normal Development of B Cells Through a BCMA-Independent Pathway . In: Science . tape 293 , no. 5537 , August 14, 2001, p. 2111-2114 , doi : 10.1126 / science.1061964 .
  3. ↑ UniProt Q9Y275
  4. ↑ Thomas Korn, Mohamed Oukka: A BAFFling association between malaria resistance and the risk of multiple sclerosis . New England Journal of Medicine 2017, Volume 376, Issue 17, April 27, 2017, pages 1680-1681, doi: 10.1056 / NEJMe1700720
  5. ↑ UniProt Q9Y275
  6. ↑ Maristella Steri, Valeria Orrù, M. Laura Idda, Maristella Pitzalis, Mauro Pala, Ilenia Zara, Carlo Sidore, Valeria Faà, Matteo Floris, Manila Deiana, Isadora Asunis, Eleonora Porcu, Antonella Mulas, Maria G. Piras, Monia Lobina, Sandra Lai, Mara Marongiu, Valentina Serra, Michele Marongiu, Gabriella Sole, Fabio Busonero, Andrea Maschio, Roberto Cusano, Gianmauro Cuccuru, Francesca Deidda, Fausto Poddie, Gabriele Farina, Mariano Dei, Francesca Virdis, Stefania Olla, Maria A. Satta, Mario Pani, Alessandro Delitala, Eleonora Cocco, Jessica Frau, Giancarlo Coghe, Lorena Lorefice, Giuseppe Fenu, Paola Ferrigno, Maria Ban, Nadia Barizzone, Maurizio Leone, Franca R. Guerini, Matteo Piga, Davide Firinu, Ingrid Kockum, Izaura Lima Bomfim , Tomas Olsson, Lars Alfredsson, Ana Suarez, Patricia E. Carreira, Maria J. Castillo-Palma, Joseph H. Marcus, Mauro Congia, Andrea Angius, Maurizio Melis, Antonio Gonzalez, Marta E. Alarcón Riquelme, Berta M. da Silva , Maurizio Marchini, Maria G. Danieli, Stef ano Del Giacco, Alessandro Mathieu, Antonello Pani, Stephen B. Montgomery, Giulio Rosati, Jan Hillert, Stephen Sawcer, Sandra D'Alfonso, John A. Todd, John Novembre, Gonçalo R. Abecasis, Michael B. Whalen, Maria G. Marrosu, Alessandra Meloni, Serena Sanna, Myriam Gorospe, David Schlessinger, Edoardo Fiorillo, Magdalena Zoledziewska, Francesco Cucca: Overexpression of the Cytokine BAFF and Autoimmunity Risk New England Journal of Medicine 2017, Volume 376, Issue 17 of April 27, 2017, pages 1615-1626, doi: 10.1056 / NEJMoa1610528