Understanding Autoantibodies in Autoimmunity
Autoimmune diseases are mediated by an attack of the body’s cells and tissues by its own immune system. The autoimmune attack involves different elements of the immune system. In some diseases the autoimmune response is mediated predominantly by T cells (Type 1 Diabetes), while in other diseases the autoimmune response is mediated mainly by B cells and their autoantibodies (Systemic Lupus Erythematosus).
Autoantibodies are found in many autoimmune disorders and can be involved in the pathogenesis through different mechanisms:
Diseases studied by the Hampe lab:
Type 1 diabetes is characterized by pancreatic beta cell destruction by a T-cell dominated autoimmune reaction leading to absolute insulin deficiency.
Autoimmune neurological disorders:The autoimmune neurological disorder Stiff Person Syndrome (SPS) presents autoantibodies directed to the 65kDa isoform of glutamate decarboxylase (GAD65Ab). GAD65 catalyzes the formation of the inhibitory neurotransmitter GABA. It is primarily expressed in the central nervous system and in the insulin-producing beta cells of the pancreas. While its role in neurotransmission is well understood, its function in the pancreatic beta cells remains an enigma.
Pathogenic role of GAD65Ab
GAD65Ab in SPS:A pathogenic role GAD65Ab in Stiff Person Syndrome and other GAD65Ab-associated movement disorders has been suggested based on the finding that GAD65Ab in this disease inhibit the enzymatic activity of GAD65 and that SPS patients have decreased levels of GABA. Rats that are intracerebellar injected with GAD65Ab show significant changes in their neurophysiology and their behavior.
Based on our findings we developed the model of a pathogenic effect of GAD65Ab on GABAergic neurotransmission in the cerebellum:
Schematic diagram of GAD65Abs in cerebellar circuits:Pathogenic GAD65Ab acts on the terminals of GABAergic neurons to reduce GABA release. The decrease of GABA release alters the activities of PCs and cerebellar nuclei neurons, resulting in disorganized outputs to motor control centers. PC: Purkinje cells, GABAergic In: GABAergic interneurons, PF; parallel fibers, MF; mossy fibers. Arrows indicate flow of signals through the cerebellum. Excitatory neurons are indicated by white circles, while inhibitory neurons by black circles.
Current and Recent Lab Members
Chris Hampe, PhD
Xin Wang, MD, PhD
UW Medicine Diabetes Institute
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