Biomedical subjects

Véronique Fremeaux-Bacchi

Publications and source records attributed to Véronique Fremeaux-Bacchi.

3 recordsLinked to original sources

PubMed2006

Genetic and functional analyses of membrane cofactor protein (CD46) mutations in atypical hemolytic uremic syndrome.

Hemolytic uremic syndrome (HUS) is characterized by the triad of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. The non-Shiga toxin-associated HUS (atypical HUS [aHUS]) has been shown to be a disease of complement dysregulation. Mutations in the plasma complement regulators factor H and factor I and the widely expressed membrane cofactor protein (MCP; CD46) have been described recently. This study looked for MCP mutations in a panel of 120 patients with aHUS. In this cohort, approximately 10% of patients with aHUS (11 patients; nine pedigrees) have mutations in MCP. The onset typically was in early childhood. Unlike patients with factor I or factor H mutations, most of the patients do not develop end-stage renal failure after aHUS. The majority of patients have a mutation that causes reduced MCP surface expression. A small proportion expressed normal levels of a dysfunctional protein. As in other studies, incomplete penetrance is shown, suggesting that MCP is a predisposing factor rather than a direct causal factor. The low level of recurrence of aHUS in transplantation in patients with MCP mutations is confirmed, and the first MCP null individuals are described. This study confirms the association between MCP deficiency and aHUS and further establishes that a deficiency in complement regulation, specifically cofactor activity, predisposes to severe thrombotic microangiopathy in the renal vasculature.

Adolescent↗

PubMed2006

[Complement component deficiencies in human disease].

The complement system, composed of several plasma and membrane proteins, is an integral part of the innate immune system and plays a role in inflammatory response, destruction of infectious agents, elimination of immune complexes, and control of the specific (adaptive) immune response. Hereditary deficiencies of complement components are relatively rare and associated with susceptibility to a wide variety of clinical diseases. Complement components may be target of antibodies (anti-C1q, factor H, C3 alternative convertase, or C3NeF autoantibodies or anti-C1 inhibitor antibodies) that lead to acquired deficiencies. Testing the complement system is especially necessary in patients with autoimmune diseases, some kidney diseases, recurrent infections (especially meningococcal), and angioedema. Precise clinical descriptions of the phenotypes associated with these deficiencies and their molecular diagnosis are necessary to improve our understanding of the role that the complement system plays in the physiopathological mechanisms of these diseases and to propose the most specific treatment for them.

Autoimmune Diseases↗

PubMed2002

[Pathophysiology of thrombotic microangiopathies: current understanding].

Thrombotic microangiopathies (TMA) encompass various severe diseases characterized by microangiopathic hemolytic anemia and peripheral thrombocytopenia, associated with fever, neurological signs and renal involvement. Microvascular thrombosis is the typical lesion, and results in tissue ischemia. Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are the two most classical forms. These two entities are clinically and histopathologically closely related. There is a body of evidence suggesting that endothelial cell injury is the initial event in TTP and HUS, and that it may be related to a large number of triggering factors, such as infection, connective tissue disease, drugs, cancer and chemotherapy, transplantation, and pregnancy. Endothelial cell injury enhances the release of ultra large forms of von Willebrand factor (ULvWF) multimers and other prothrombotic agents, such as plasminogen activator inhibitor and platelet activating factor, whereas it decreases the release of prostaglandin-I2, a strong inhibitor of platelet aggregation. Recently however, it has been shown that TTP and HUS were pathophysiologically distinct. Actually, TTP is associated with a deficiency in von Willebrand factor-cleaving protease, an enzyme involved in cleavage of ULvWF into circulating 200 kDa and 350 kDa fragments. This deficiency may be either congenital or acquired, and then related to an IgG inhibitory autoantibody. This protease deficiency may account for the high amounts of plasmatic ULvWF in TTP patients. In HUS, vWF-cleaving protease activity is found normal. HUS encompasses two distinct entities. Epidemic, or diarrhea-associated HUS, is associated with verotoxin or Shiga toxin-associated enterobacteriaceae. These toxins are directly responsible for endothelial cell injury. Sporadic HUS (also termed atypical HUS in children) is closely related to TTP, and shares the same triggering factors. Familial HUS has been associated in some cases with hypocomplementemia and factor H dysfunction, the pathophysiological role of which remains unclear. The study of the different triggering factors and predisposing factors may be useful to define different subsets of TMA, that may be characterized by their course and prognosis.

ADAM Proteins↗