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Linking Primary Immunodeficiencies with Transplant Medicine: Basic Science from ESID Meeting

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Javier Carbone, MD, PhD
University Hospital Gregorio Marañon

The 16th Biennial Meeting of the European Society for Immunodeficiencies (ESID), held in Prague, Czech Republic on October 26, 2014, encompassed innovations in immunobiology, genetics, diagnostics and treatment of primary immunodeficiencies (PID). Advances in medical research have led to the identification of more than 240 genes which cause different forms of PID. Defects in such processes are often responsible for life-threatening disorders.

Understanding the essential signals that govern development and maturation of T, B, NK, other lymphocytes and cells may help us to understand the function of the distinct effector functions that are involved in solid organ transplantation.

The ubiquitin-proteasome pathway has a critical role in maintaining the homeostasis of cells and is believed to be involved in the development and progression of inflammatory diseases. Recent observations suggest that the ubiquitin-proteasome system contributes to the pathophysiology of myocardial ischemia-reperfusion injury. During the first plenary session, Aaron Ciechanover, winter of the 2004 Nobel Prize in Chemistry, reviewed the two step ubiquitin mediated proteolytic activation of NF-kB. The transcription factor NF-kB controls many processes including allograft rejection.

How do we integrate microRNA into our current understanding of the networks that govern gene expression and cellular identity? Can we discover new genes and pathways involved in biological processes of interest through the study of microRNAs and their targets? Mark Ansel answered these questions in his talk about understanding the immune system through microRNA. Within the past decade, the field of immunology has increasingly intersected with the field of microRNA biology. The relationships between microRNAs and their gene targets, in the context of heart and lung transplantation, warrants further investigation.

Gilliam Griffiths talked about the Immunological Synapse. Her talk was amazing; from TCR recognition to centrosome polarization for killing of target cells. You were able to see how centrosome scans the synapse and identifies the point for secretion of cytotoxicity mediators.

NK cell-mediated cytotoxicity is involved in allograft rejection and autoimmune diseases. Deletion of the dedicator of cytokinesis 2 (DOCK2), a regulator of actin cytoskeleton in lymphocytes, suppresses cardiac allograft rejection in mice. In the plenary session entitled "PID without borders", Luigi Notarangelo outlined that DOCK-2 deficiency affects NK cell cytotoxicity by perturbing multiple signaling pathways including impaired degranulation. Because DOCK2 expression is limited to hematopoietic cells, DOCK2 might be considered as a potential novel therapeutic target for controlling rejection.

In the parallel session, "The Border between Innate and Adaptive Immunity", James Di Santo reviewed the definition of innate-liked lymphocytes (ILCs). ILCs belong to an emerging family of innate immune cells that have been implicated in playing critical roles in human health and disease. ILC populations can be divided into three groups based on shared phenotypic and functional properties: ILC1 (including classical NK cells, non NK CD127+ and CD127- cells), ILC2 and ILC3 cells.

Eric Vivier discussed differential control of extracytoplasmic bacterial infections by subsets of ILCs. Common variable immunodeficiency patients who develop pneumonia, sepsis or granuloma, are found to have lower levels of NK cells (<50 cells/mL). This is an interesting observation. Low NK cell levels have also been observed following heart transplantation.

The protein cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential negative regulator of immune responses. CTLA-4 deficiency was presented as a novel autosomal dominant immune dysregulation syndrome by Desiree Schubert (abstract 360). Mutations in CTLA4 resulting in CTLA-4 haploinsufficiency or impaired ligand binding result in disrupted T and B cell homeostasis and a complex immune dysregulation syndrome (decreased circulating B cell numbers, hypogammaglobulinemia, recurrent infections, impaired T-reg suppressive function and multiple autoimmune clinical features).

Toll interleukin 1 receptor domain containing adaptor (TIRAP) is an adaptor acting downstream from TLR2 and TLR4. TIRAP-dependent TLR2 immunity is important for the control of staphylococcal infection in children lacking anti-staphylococcal lipoteichoic acid antibodies (anti-LTA). Anne Puel presented this interesting example of how the combined effect of two inherited deficiencies, anti-LTA and TIRAP, which is redundant in host defense, accounts for staphylococcal disease (abstract 92).

The transfer of knowledge from PID basic science to other clinical areas might improve our level of understanding of old and emerging problems. ■

Disclosure Statement: The author has no conflicts of interest to disclose.

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