Supervisors info:
Ευθυμιόπουλος Σπυρίδων, Καθηγητής Φυσιολογίας Ζώων και Ανθρώπου-Νευροβιολογίας, Βιολογίας, ΕΚΠΑ
Σταματάκης Αντώνης, Αναπληρωτής Καθηγητής Βιολογίας-Βιολογίας Συμπεριφοράς, Νοσηλευτικής,ΕΚΠΑ
Ρούτσιας Ιωάννης, Επίκουρος Καθηγητής Μικροβιολογίας, Ανοσολογίας, Ιατρικής ΕΚΠΑ
Summary:
Stiff Person Syndrome (SPS) is a rare, disabling autoimmune CNS disorder, associated with a variety of autoantibodies that target antigens expressed in neurons of the brain and spinal cord, at synapses using the neurotransmitter gamma-aminobutyric acid (GABA).
Based on the presumed pathogenesis of SPS, the two main therapeutic approaches are: 1)GABA-enhancing drugs and 2)immunomodulating or immunosuppressant agents. Anti-B cell therapies using humanized monoclonal antibodies directed against CD20+ cells, have been proposed as a rational approach to modulating autoreactive and clonally expanded B cells in the CNS in SPS. Several case reports have indicated that rituximab, a B-cell depleting monoclonal antibody, was well-tolerated and appeared to exert long-lasting clinical remissions, although circulating antibody titers did not decline, although in other studies rituximab was found to be ineffective overall.
Rituximab is a mouse/human chimeric antibody that mediates complement-dependent cell lysis (CDCC) in the presence of human complement, and mainly antibody-dependent cellular cytotoxicity (ADCC), with human effector cells through Fcγ receptors of IgG. SNPs in the coding region of a gene, often result in amino acid changes that may alter the functioning of the affected proteins. Certain SNPs in the coding regions of the FCGR2A and FCGR3A genes appear to have clinical significance as they have been reported to correlate with responses to therapeutic mAbs. An important role for the FcγR phenotype, is indicated by the observation that effector cells from donors homozygous for FCGR3A 158 V (V/V) and FCGR2A 131 H(H/H) bound more IgG compared with cells from donors who were homozygous for FCGR3A 158 F (F/F) and FCGR2A 131 R(R/R).
In our study, we tested the genotype of SPS patients, who were treated with rituximab and placebo and our aim was to identify whether they had response to rituximab are homozygous for FCGR3A 158 V and FCGR2A 131 H. They were homozygous V/V, homozygous F/F for FCGR3A gene and heterozygous F/V for FCGR2A gene accordingly. There is no correlation of FCGR3A and FCGR2A receptor with highest affinity and response to rituximab.
Myelin oligodendrocyte glycoprotein (MOG) has been identified as a target of demyelinating autoantibodies in inflammatory demyelinating diseases of the CNS, such as paediatric multiple sclerosis. Anti-AQP4 antibodies are specific markers and pathogenetic factors for neuromyelitis optica (NMO) and NMO spectrum of disorders. Systemic lupus erythematosus (SLE) is a chronic, relapsing–remitting systemic autoimmune disease. Antiphospholipid syndrome (APS), is an autoimmune, hypercoagulable state caused by antiphospholipid antibodies. Pathogenic anti-AQP4 autoantibodies were found in SLE patients, without the development of any clinical or radiological signs of NMOSD.
Cell-based immunoassays using MOG expressed in mammalian cells have demonstrated the presence of MOG and AQP-4 antibodies in SLE and APS patients with any sign of demyelination and neurological symptoms. 40 SLE patients were screened and 1 was seropositive for MOG autoantibodies. Also, 8 APS patients were screened and they were 2 seropotive for MOG and 1 seropositive for AQP-4 autoantibodies.
Anti-AQP4 and anti-MOG antibodies from non neurological SLE and APS patients can persist and although they induce complement-mediated astrocytic cytotoxicity, they do not cause disease.
Keywords:
biomarkes, sps, autoimmunity, response, therapy, autoantibodies
