Immunoregulation And Immunointervention in Transplantation and Autoimmunity
Jean Harb
Research Scientist

Assistant Professor

My current research is focused on the role of the glycosylation and especially sialylation of the immunoglobulins G in their functionality. The IgG sialylation of the Fc fragment modulates its interaction with different activator or inhibitor receptors expressed on several immune cells. Studies are performed in kidney transplanted patients having Donor specific anti-HLA antibodies in correlation with the antibodies mediated rejection. Another study is performed on the role of this sialylation in patients suffering from monoclonal gammopathy of undetermined significance (MGUS) or Multiple myeloma (Collaboration with CICRNA-INSERM U1232) .

Description

It is well known now that the glycosylation of the Fc fragment of the immunoglobulins is essential to their binding to the FCgR receptors on innate immune cells. These receptors are activators or inhibitors, depending on the intracellular patterns. The IVIg immunoglobulins are used since 30 years in the treatment of autoimmune diseases due to their immunomodulatory effects. Several hypotheses have been claimed to explain this effect. Kaneko et al. (2006) proved that the efficiency of these IVIg is due to the sialylation of the Fc fragment. The treatment of these immunoglobulins with neuraminidase abrogates their effect.

In organ transplantation, the presence of donor specific antibodies (DSA) against Class I or II anti-HLA antigens is a risk factor known since long time (Lefaucheur et al., 2010). 50% of patients develop de novo DSA (Ferrari-lacraz et al. 2012). These antibodies have a deleterious impact on the graft, with a risk of graft loss due to antibody mediated rejection (AMR). (Terasaki and Ozawa, 2005; Lachmann et al. 2009, Mao et al. 2007; Hourmant et al., 2005). However, as demonstrated by Lefaucheur, some patients conserve a good renal function despite the presence of these DSA.

We studied the sialylation of these antibodies by ELISA using Sambucusnigra Agglutinin (SNA). The sialylation of IgGs was higher at the time of transplantation in DSA+AMR- patients than in DSA+AMR+ (p=0.029). This phenomenon is also observed at time of DSA appearance but was not satistically significant. The purified sialylated IgGs were used to detect the anti-HLA antibodies by the Luminex technique. We observed a higher sialylation of the anti-class I antibodies in DSA+AMR- than in DSA+AMR+ patients (p=0.06) suggesting that the sialylation of these antibodies could explain their low pathogenicity in transplanted patients.

 Multiple myeloma (MM) is characterized by >10% malignant plasma cells in the bone marrow, which secrete >30g/L of monoclonal immunoglobulin (mc Ig). MM is preceded by an asymptomatic stage called "monoclonal gammopathy of undetermined significance" (MGUS), when plasma cells are <10% and mc Ig production <30g/L. A chronic inflammatory state in MGUS and Myeloma could directly influence the mc Ig structure produced in these pathologies. We undertook since June 2015 the study of the sialylation of the monoclonal as well as the polyclonal antibodies purified from patients suffering from MGUS or Myeloma. Our results showed that mc IgGs were found to be hyposialylated for 81.6% of MGUS and MM patients (80/98). For 37% of MM patients, the purified polyclonal IgGs were also significantly hyposialylated, like mc IgGs. This suggests a more severe inflammation status for these patients. (Bosseboeuf et al, 2016)

The level of pro-inflammatory cytokines (HGF, IL-11, IL-6, IL-10, IL-12) secreted in the serum of these patients will be performed and a correlation between the state inflammatory of these pathologies and the sialylation state of the mc Ig will be drawn.