ABSTRACT
A homozygous mutation in a splice site of the CD81 gene was identified previously in a patient, as the cause in a case of common variable immune deficiency (CVID). CD19 expression is reduced in mice that lack CD81; however, B cells in this patient lacked completely CD19 surface expression. The mutation led to an absence of the CD81 protein on the cell surface and it was assumed that the CD81 protein was not produced. Here we demonstrate that a truncated human CD81 mutant (CD81mut) was actually produced, but retained intracellularly. We also demonstrate that the truncated CD81mut protein is in close proximity to the intracellularly sequestered CD19. However, this interaction does not enable normal CD19 maturation and surface expression. In addition, we show that specific domains of CD81 enable retrieval and trafficking of human CD19 to the cell surface. Finally, we demonstrate that surface expression of CD19 requires CD81, even in non-B cells.
Subject(s)
Antigens, CD19/metabolism , Tetraspanin 28/metabolism , Animals , B-Lymphocytes/metabolism , Cell Line , Cell Membrane/metabolism , Hepatocytes/metabolism , Humans , Mice , Mutation , Protein Transport , Tetraspanin 28/geneticsABSTRACT
We have previously shown that several phosphodiesterase (PDE) subtypes are up-regulated in muscles and lymph node cells (LNC) of rats with experimental autoimmune myasthenia gravis (EAMG). In the present study we investigated PDE expression during the course of EAMG and experimental allergic encephalomyelitis (EAE) and found that the up-regulated expression of selected PDE subtypes in both experimental models is correlated with disease severity. In EAMG, PDE expression is correlated also with muscle damage. A similar up-regulation of PDE was also observed in the respective human diseases, MG and multiple sclerosis (MS). Our findings suggest that change in PDE expression levels is a general phenomenon in autoimmune diseases and may also be used as a marker for disease severity.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental/enzymology , Multiple Sclerosis/enzymology , Myasthenia Gravis, Autoimmune, Experimental/enzymology , Myasthenia Gravis/enzymology , Phosphoric Diester Hydrolases/metabolism , Adolescent , Adult , Animals , Biomarkers/analysis , Biomarkers/blood , Child , Disease Models, Animal , Disease Progression , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/physiopathology , Female , Humans , Isoenzymes/metabolism , Multiple Sclerosis/immunology , Multiple Sclerosis/physiopathology , Muscular Atrophy/enzymology , Muscular Atrophy/immunology , Muscular Atrophy/physiopathology , Myasthenia Gravis/immunology , Myasthenia Gravis/physiopathology , Myasthenia Gravis, Autoimmune, Experimental/immunology , Myasthenia Gravis, Autoimmune, Experimental/physiopathology , Predictive Value of Tests , Rats , Rats, Inbred Lew , Severity of Illness Index , Up-Regulation/immunology , Young AdultABSTRACT
Accumulating evidence suggests that autoimmunity against neuronal proteins is important for MS pathogenesis. We have characterized T- and B-cell responses associated with experimental autoimmune encephalomyelitis (EAE) induced in Lewis rats with recombinant beta-Synuclein (betaSync), a neuronal component. The encephalitogenic betaSync-specific T cells recognize a single immunodominant region with an epitope delineated at amino acids 97-105; B-cell specificity is more widespread, albeit directed mostly to the C-terminus of betaSync. Most interestingly, betaSync-induced autoimmune T- and B-cell responses spread not only to other neuronal antigens but also to myelin encephalitogens, raising the possibility that anti-neuronal immune attacks could also result in demyelination.
