Guillain-Barré syndrome: expanding the concept of molecular mimicry

Guillain-Barré syndrome (GBS) after Campylobacter jejuni infection is a true case of molecular mimicry–driven disease. The immunopathogenesis of GBS sheds new light on the multimolecular identities of self-antigens. The glycan nature of mimicry epitopes that drives antibody class switching to IgG subclasses challenges rigid concepts of thymus-dependent and -independent B cell responses because antiglycolipid antibodies are mainly IgG1 and IgG3, albeit short-lasting. Combinatorial chemoenzymatic technologies and arrays allow the development of novel diagnostic and research tools to identify antibodies against mono- and multimeric carbohydrate epitopes. A certain degree of dissimilarity may be required for the occurrence of molecular mimicry in Campylobacter jejuni–associated GBS. Guillain-Barré syndrome (GBS) is a rapidly progressive, monophasic, and potentially devastating immune-mediated neuropathy in humans. Preceding infections trigger the production of cross-reactive antibodies against gangliosides concentrated in human peripheral nerves. GBS is elicited by at least five distinct common bacterial and viral pathogens, speaking to the notion of polymicrobial disease causation. This opinion emphasizes that GBS is the best-supported example of true molecular mimicry at the B cell level. Moreover, we argue that mechanistically, single and multiplexed microbial carbohydrate epitopes induce IgM, IgA, and IgG subclasses in ways that challenge the classic concept of thymus-dependent (TD) versus thymus-independent (TI) antibody responses in GBS. Finally, we discuss how GBS can be exemplary for driving innovation in diagnostics and immunotherapy for other antibody-driven neurological diseases. Guillain-Barré syndrome (GBS) is a rapidly progressive, monophasic, and potentially devastating immune-mediated neuropathy in humans. Preceding infections trigger the production of cross-reactive antibodies against gangliosides concentrated in human peripheral nerves. GBS is elicited by at least five distinct common bacterial and viral pathogens, speaking to the notion of polymicrobial disease causation. This opinion emphasizes that GBS is the best-supported example of true molecular mimicry at the B cell level. Moreover, we argue that mechanistically, single and multiplexed microbial carbohydrate epitopes induce IgM, IgA, and IgG subclasses in ways that challenge the classic concept of thymus-dependent (TD) versus thymus-independent (TI) antibody responses in GBS. Finally, we discuss how GBS can be exemplary for driving innovation in diagnostics and immunotherapy for other antibody-driven neurological diseases. end-feet of astrocyte extensions; contribute to the formation and function of the CNS blood–brain barrier. axon plasma membrane. rare variant of GBS presenting as peripheral neuropathy (usually MFS) with weakness of muscles involved in eye movements but progressing to limb weakness and lowered consciousness due to involvement of the brainstem as part of the CNS. Bickerstaff brainstem encephalitis, like MFS, is associated with the presence of antiganglioside GQ1b antibodies. cell and tissue structures controlling access of soluble molecules, including pathogenic autoantibodies to the nerve. This barrier does not prevent infiltration of leukocyte subsets, because these behave distinctly from soluble molecules. The blood–nerve barrier is less tight at nerve roots, ganglia, and nerve terminals. eight-polypeptide chain subcomponent of C1, the first component of the complement protein cascade, with a characteristic six-tulip-like shape. The binding of the Fc components of closely arrayed antibody molecules to C1q initiates the classic pathway of complement activation, including activation of the membrane attack complex. In humans, C1q can be bound by IgM, IgG1, IgG2, and IgG3, but not by other isotypes. sialic acid–containing glycosphingolipids, composed of ceramide and oligosaccharide; enriched in lipid rafts and highly expressed in nervous tissue. Frequent attachment site for microbial toxins. immune-mediated peripheral neuropathy, usually triggered by a preceding infection; clinically characterized by rapidly progressive bilateral muscle weakness. GBS is clinically diverse and includes the predominant sensorimotor form, pure motor form, MFS, and other forms. The peripheral neuropathy is characterized by demyelination, axonal degeneration, or both. The specificity of the antibodies to gangliosides is associated with the clinical form and neuropathy subtype. endotoxin expressed by C. jejuni. LOS is chemically distinct from lipopolysaccharide because it lacks the repetitive O antigen. LOS consists of lipid A and an inner and outer core of oligosaccharides. Sialylated LOS strongly activates Toll-like receptor TLR4. clinical variant of GBS characterized by oculomotor neuropathy and weakness of muscles involved in eye movements causing complaints of double vision; associated with antiganglioside GQ1b antibodies. formal medical definition used in this opinion is the structural similarities of host epitopes and pathogen epitopes that elicit autoreactive T and/or B cells driving pathogenesis. Postulates of Koch and Witebsky can be productively applied to validate suspected molecular mimicry. in the CNS, dominated by inflammation of the optic nerve (optic neuritis) and the spinal cord (myelitis). Previously known as Devic disease or neuromyelitis optica. incisures in the myelin sheath allowing saltatory pulse conduction. In the peripheral nervous system, gangliosides are concentrated and/or more accessible to autoantibodies at the nodes of Ranvier. at both sides of the node of Ranvier, the myelin sheath is not compacted and is filled with cytoplasm of the myelinating Schwann cell (peripheral nervous system) or oligodendrocyte (CNS), spirally wrapped around the axon. Paranodal spirals resemble loops in cross-section. a conserved molecular motif such as lipopolysaccharides or lipoproteins, present on pathogens and recognized by a pattern recognition receptor. clinical GBS variant; patients have muscle weakness but no sensory deficits; associated with antigangliosides GM1 and GD1a antibodies. occurs along myelinated axons; involves the propagation of electrical pulses from one node of Ranvier to another. Conduction velocity along myelinated fibers is much faster than along nonmyelinated fibers (80–120 m/s versus 0.5–2.0 m/s). predominant clinical GBS form; patients have sensory deficits in combination with muscle weakness. mutations in the variable domains of immunoglobulin genes that occur during germinal center responses. cells of the peripheral nervous system that myelinate one axon, while CNS oligodendrocytes insulate and provide saltatory pulse conduction by wrapping cytoplasmic extensions around up to 70 axons. Schwann cells also surround small-diameter axons that are nonmyelinated. requirements for B cell activation and induction of antibody responses against antigens, based on classic thymectomy experiments and transgenic mice. As NK cell development also occurs in the thymus, a TD response can also occur without T cell help. a disease can be regarded as autoimmune based on direct evidence that it can be transferred by a pathogenic antibody or T cells, indirect evidence based on the development of autoimmune disease in experimental animals, or conditional evidence from clinical signs and patient symptoms.