Campylobacter jejuni induces autoimmune peripheral neuropathy via Sialoadhesin and Interleukin-4 axes

Abstract

Campylobacter jejuni is a leading cause of gastroenteritis that has been causally linked with development of the autoimmune peripheral neuropathy Guillain Barré Syndrome (GBS). Previously, we showed that C. jejuni isolates from human enteritis patients induced Type1/17-cytokine dependent colitis in interleukin-10 (IL-10) −/− mice, while isolates from GBS patients colonized these mice without colitis but instead induced autoantibodies that cross-reacted with the sialylated oligosaccharide motifs on the LOS of GBS-associated C. jejuni and the peripheral nerve gangliosides. We show here that infection of IL-10 −/− mice with the GBS but not the colitis isolate led to sciatic nerve inflammation and abnormal gait and hind limb movements, with character and timing consistent with this syndrome in humans. Autoantibody responses and associated nerve histologic changes were dependent on IL-4 production by CD4 T cells. We further show that Siglec-1 served as a central antigen presenting cell receptor mediating the uptake of the GBS isolates via interaction with the sialylated oligosaccharide motifs found specifically on the LOS of GBS-associated C. jejuni , and the ensuing T cell differentiation and autoantibody elicitation. Sialylated oligosaccharide motifs on the LOS of GBS-associated C. jejuni therefore acted as both the Siglec-1-ligand for phagocytosis, as well as the epitope for autoimmunity. Overall, we present a mouse model of an autoimmune disease induced directly by a bacterium that is dependent upon Siglec-1 and IL-4. We also demonstrate the negative regulatory role of IL-10 in C. jejuni induced autoimmunity and provide IL-4 and Siglec-1 blockade as potential therapeutic interventions against GBS.

Dissecting the abilities of murine Siglecs to interact with gangliosides

“…Indeed, gangliosides within the membrane of HIV, Ebola, and SARS-CoV-2 are known to engage Siglecs and facilitate immune evasion and infection ( 31 , 32 , 33 ). Campylobacter jejuni uses ganglioside-like oligosaccharides, as a form of host mimicry, to engage Siglecs ( 41 , 42 ). Moreover, cancerous cells release EVs with higher ganglioside content likely to protect themselves from the immune system ( 43 ).…”

Campylobacter jejuni-Associated Hemophagocytic Lymphohistiocytosis and Guillain-Barre Syndrome: A Case Report

“…Siglec-1 is a type1 transmembrane protein and belongs to the Sialic acid binding Ig-like lectin family. It plays a critical role in the maturation of colonic T cells and in the elicitation of autoantibodies ( 18 ). Furthermore, a recent study has found that GBS patients exhibit defective signaling of Siglec-10, an inhibitory receptor expressed by B cells, which may give rise to aberrant B cell responses against gangliosides or LOS.…”

The microbiota–gut–brain axis and neurodevelopmental disorders

“…For example, in an early study, gut inoculation of Campylobacter jejuni in mice has been reported to result in direct activation of the vagal sensory ganglia and the nucleus tractus solitarius (NTS) in the medulla oblongata ( Goehler et al ., 2005 ). Campylobacter jejuni is the leading cause of bacterial diarrhoeal disease in many areas of the world ( Burnham and Hendrixson, 2018 ; Malik et al ., 2022 ) and its administration has been reported to induce anxiety-related behaviors ( Lyte et al, 2002 ). Campylobacter jejuni is also causally linked with the development of the autoimmune peripheral neuropathy Guillain Barré Syndrome (GBS) ( Malik et al ., 2022 ).…”

“…Campylobacter jejuni is the leading cause of bacterial diarrhoeal disease in many areas of the world ( Burnham and Hendrixson, 2018 ; Malik et al ., 2022 ) and its administration has been reported to induce anxiety-related behaviors ( Lyte et al, 2002 ). Campylobacter jejuni is also causally linked with the development of the autoimmune peripheral neuropathy Guillain Barré Syndrome (GBS) ( Malik et al ., 2022 ). Such responses caused by C .…”