Bridging the gap: Insights in the immunopathology of Lyme borreliosis

Abstract

Lyme borreliosis (LB), caused by Borrelia burgdorferi sensu lato (Bbsl) genospecies transmitted by Ixodes spp. ticks, is a significant public health concern in the Northern Hemisphere. This review highlights the complex interplay between Bbsl infection and host-immune responses, impacting clinical manifestations and long-term immunity. Early localized disease is characterized by erythema migrans (EM), driven by T-helper 1 (Th1) responses and proinflammatory cytokines. Dissemination to the heart and CNS can lead to Lyme carditis and neuroborreliosis respectively, orchestrated by immune cell infiltration and chemokine dysregulation. More chronic manifestations, including acrodermatitis chronica atrophicans and Lyme arthritis, involve prolonged inflammation as well as the development of autoimmunity. In addition, dysregulated immune responses impair long-term immunity, with compromised B-cell memory and antibody responses. Experimental models and clinical studies underscore the role of Th1/Th2 balance, B-cell dysfunction, and autoimmunity in LB pathogenesis. Moreover, LB-associated autoimmunity parallels mechanisms observed in other infectious and autoimmune diseases. Understanding immune dysregulation in LB provides insights into disease heterogeneity and could provide new strategies for diagnosis and treatment.

Keywords: Autoimmunity; Borrelia burgdorferi; Immune dysregulation; Inflammation; Lyme borreliosis; Th1/Th2 Balance.

Figure 1

Clinical manifestations and inflammatory signatures of Lyme borreliosis. Clinical manifestations are divided into early localized disease (erythema migrans), early disseminated disease (Lyme carditis and Lyme neuroborreliosis), late disseminated disease (acrodermatitis chronica atrophicans and Lyme arthritis), and post‐treatment persisting complaints (post‐treatment Lyme disease syndrome).

Figure 2

Inhibition of long‐term immunity by Borrelia burgdorferi sensu stricto. Accumulation of B. burgdorferi ss in the lymphoid structures in mice induces B cell proliferation and differentiation to short‐lived antibody‐secreting plasma cells producing low affine IgM but inhibits the formation of long‐lived memory B cells and plasma cell formation induced by follicular dendritic cells and follicular helper T cells. This results in involution of the germinal center, decreased high affine IgG production, and lack of immune memory.

Figure 3

Development of autoantibodies and autoreactive T cells via molecular mimicry. High similarity between spirochetal antigens and autoantigens heat shock protein (hsp) family, myosin, myelin basic protein (MBP), human leukocyte function‐associated antigen‐1 (hLFA1), annexin A2, endothelial growth cell factor (EGCF), apolipoprotein B‐100 (apoB100), matrix metalloproteinase‐10 (MMP10), and CNS antigens result in the production of autoantibodies due to molecular mimicry. In the presence of Borrelia burgdorferi ss and IFN‐γ fibroblasts and fibroblast‐like cells present autoantigens to naïve CD4⁺ T cells resulting in the proliferation of autoreactive T cells. Autoreactive immune responses potentially contribute to Lyme borreliosis disease manifestations, such as Lyme arthritis, Lyme neuroborreliosis, and post‐treatment Lyme disease syndrome.