Autoimmunity occurs when the immune system recognizes and attacks host tissue. In addition to genetic factors, environmental triggers (in particular viruses, bacteria and other infectious pathogens) are thought to play a major role in the development of autoimmune diseases. In this review, we (i) describe the ways in which an infectious agent can initiate or exacerbate autoimmunity; (ii) discuss the evidence linking certain infectious agents to autoimmune diseases in humans; and (iii) describe the animal models used to study the link between infection and autoimmunity.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2249.2008.03834.x

The role of infections in autoimmune disease.

Hsp60 in eukaryotes is considered typically a mitochondrial chaperone (also called Cpn60) but in the last few years it has become clear that it also occurs in the cytosol, the cell surface, the extracellular space, and in the peripheral blood. Studies with prokaryotic models have shown that Hsp60 plays a role in assisting nascent polypeptides to reach a native conformation, and that it interacts with Hsp10 (which also resides in the mitochondria and is also named Cpn10). In addition to its role in polypeptide folding in association with Hsp10, other functions and interacting molecules have been identified for Hsp60 in the last several years. Some of these newly identified functions are associated with carcinogenesis, specifically with tumor cell survival and proliferation. Thus, assessing the levels of Hsp60 in tumor cells and in sera of cancer patients is becoming an attractive area of investigation aiming at the development of means for practical applications in clinical oncology. Since Hsp60 participat...

Hsp60 expression, new locations, functions, and perspectives for cancer diagnosis and therapy

The highly conserved and ubiquitous heat shock proteins (HSP) are essential for the cellular homeostasis and efficiently trigger cellular responses to stress conditions. Both microbial and human HSP act as dominant antigens in numerous infectious and autoimmune diseases such as atherosclerosis, inducing a strong immune-inflammatory response. In the present study, the surface localization of HSP60 on stressed and unstressed human umbilical venous endothelial cells (HUVECs) was investigated using sensitive high resolution microscopy methods and flow cytometry. Confocal laser scanning microscopy (CLSM) revealed an increase of HSP60 in the mitochondria and on the surface of heat-stressed living and fixed HUVECs compared to unstressed cells. Atomic force microscopy (AFM), which has developed as sensitive surface-probe technique in biology, confirmed the presence of HSP60 on the membrane of stressed cells at an even higher lateral resolution by detecting specific single molecule binding events between the monoclonal antibody AbII-13 tethered to AFM tips and HSP60 molecules on cells. The interaction force (force required to break a single AbII-13/HSP60 bond) was 59±2 pN, which correlated nicely to the 51±1 pN measured with isolated HSP60 attached to mica surfaces. Overall, we found clear evidence for the occurrence of HSP60 on the surface of stressed HUVECs in a very similar patchy distribution pattern in living and fixed cells. The relevance of our findings with respect to the role of HSP60 in atherogenesis is discussed.

Detection of HSP60 on the membrane surface of stressed human endothelial cells by atomic force and confocal microscopy.

The purpose of this report is to offer a consensus opinion of ACVIM diplomates on the diagnosis, treatment, and prevention of Borrelia burgdorferi infections in dogs (canine Lyme disease). Clinical syndromes known to commonly be associated with canine Lyme disease include polyarthritis and glomerulopathy. Serological test results can be used to document exposure to B. burgdorferi but not prove illness. Although serum enzyme-linked immunosorbent assay/indirect fluorescent antibody assay titers can stay positive for months to years after treatment, quantitative C6 peptide antibody paired tests need more study. Serological screening of healthy dogs is controversial because it can lead to overdiagnosis or overtreatment of normal dogs, most of which never develop Lyme disease. However, serological screening can provide seroprevalence and sentinel data and stimulate owner education about tick infections and control. Although it is unknown whether treatment of seropositive healthy dogs is beneficial, the consensus is that seropositive dogs should be evaluated for proteinuria and other coinfections and tick control prescribed. Tick control can include a product that repels or protects against tick attachment, thereby helping to prevent transmission of coinfections as well as Borrelia spp. Seropositive dogs with clinical abnormalities thought to arise from Lyme disease generally are treated with doxycycline (10 mg/kg q24h for 1 month). Proteinuric dogs might need longer treatment as well as medications and diets for protein-losing nephropathy. The ACVIM diplomates believe the use of Lyme vaccines still is controversial and most do not administer them. It is the consensus opinion that additional research is needed to study predictors of illness, "Lyme nephropathy," and coinfections in Lyme endemic areas.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1939-1676.2006.tb02880.x

ACVIM small animal consensus statement on Lyme disease in dogs: diagnosis, treatment, and prevention.

Lyme disease, caused by Borrelia burgdorferi, causes a multisystem inflammatory ailment, although the precise means of tissue damage are not well understood. It is clear that the organism is present at the site of inflammation in many organs and that many of the features of the illness are relieved by antibiotic therapy. A complex interaction between spirochete and immune systems of a number of mammalian hosts, in human disease and animal models, has been described. It is clear that T cells and macrophages are intimately associated with the pathogenesis of arthritis and that immune mechanisms are involved in other aspects of disease. Inflammation directed at persistence of Borrelial antigens is a plausible explanation for persisting arthritis. Autoimmunity based on molecular mimicry may play a role in the pathogenesis of Lyme disease. Humoral immunity plays a protective role, prompting interest in vaccine development. Significant variation in certain of the outer surface proteins suggests that multiple proteins, peptides, or chimeric vaccines may be needed to provide a sufficiently broad humoral protective response.

LYME DISEASE:A Review of Aspects of Its Immunology and Immunopathogenesis

Antibodies in sera of 7 patients with neurologic manifestations of Lyme borreliosis and a monoclonal antibody (mAb H9724) to the flagellin of Borrelia burgdorferi have been shown to bind neural tissue. To identify the antibody binding site common to the B. burgdorferi flagellin and the neural tissue, we made recombinant fusion proteins expressing epitopes of flagellin. Antibodies in patients' sera and mAb H9724 bound within an 18-amino acid epitope (residues 208-225) in the central region of flagellin, whereas two other mAbs bound to epitopes mapping elsewhere in the protein. Antibodies in patients sera and mAb H9724 also bound to a human neuroblastoma cell line. Absorption of patients sera with a peptide, EGVQQEGAQQPA, corresponding to amino acids 213-224 of flagellin, inhibited binding to the neuroblastoma cell line. The data suggest that the immune response to a specific B-cell epitope within flagellin, shared by a human neuroblastoma cell line, may be involved in the pathogenesis of neuroborreliosis.

http://www.pnas.org/content/90/1/183.full.pdf

Serologic response to the Borrelia burgdorferi flagellin demonstrates an epitope common to a neuroblastoma cell line

Although Borrelia burgdorferi, the causative agent of Lyme disease, is found at the site of many disease manifestations, local infection may not explain all its features. B.
burgdorferi's flagellin cross-reacts with a component of human peripheral nerve axon, previously identified as heat shock protein 60 (HSP60). The cross-reacting epitopes are bound by a monoclonal antibody to B. burgdorferi's flagellin, H9724. Addition of H9724 to neuroblastoma cell cultures blocks in vitro spontaneous and peptide growth-factor–stimulated neuritogenesis. Withdrawal of H9724 allows return to normal growth and differentiation. Using electron microscopy, immunoprecipitation and immunoblotting, and FACS analysis we sought to identify the site of binding of H9724, with the starting hypotheses that the binding was intracellular and not identical to the binding site of II-13, a monoclonal anti-HSP60 antibody. The current studies show that H9724 binds to an intracellular target in cultured cells with negligible, if any, surface binding. We previously showed that sera from patients with neurological manifestations of Lyme disease bound to human axons in a pattern identical to H9724's binding; these same sera also bind to an intracellular neuroblastoma cell target. II-13 binds to a different HSP60 epitope than H9724; II-13 does not modify cellular function in vitro. As predicted, II-13 bound to mitochondria, in a pattern of cellular binding very different from H9724, which bound in a scattered cytoplasmic, nonorganelle-related pattern. H9724's effect is the first evidence that HSP60 may play a role in peptide-hormone–receptor function and demonstrates the modulatory potential of a monoclonal antibody on living cells.

H9724, a monoclonal antibody to Borrelia burgdorferi's flagellin, binds to heat shock protein 60 (HSP60) within live neuroblastoma cells: a potential role for HSP60 in peptide hormone signaling and in an autoimmune pathogenesis of the neuropathy of Lyme disease.

This chapter summarizes the discovery of a specific peptide sequence in heat shock protein (hsp) 60 as the molecular mimic of an immunodominant determinant in flagellin of Borrelia burgdorferi the etiological agent of Lyme disease (LD). The pathognomonic skin rash of LD, erythema migrans (EM), seen in about 50-70% of patients, usually begins as an erythematous macule or papule at the site of the tick bite. The lesion expands within a few days, often with central clearing. Approximately 8% of patients with untreated early localized LD progress to carditis, occurring within days of the onset of infection or as long as 9 months after the onset of EM. Lyme carditis causes fluctuating atrioventricular conduction defects, myopencarditis, and very mild congestive heart failure. The neuropathy associated with chronic Lyme disease is an axonopathy rather than a demyelinating neuropathy. Additional experiments are required to firmly establish our hypothesis on an anti-hsp 60 autoimmune mechanism in neurological Lyme disease.

Stephanie Williams

Papers

Serologic response to the Borrelia burgdorferi flagellin demonstrates an epitope common to a neuroblastoma cell line

H9724, a monoclonal antibody to Borrelia burgdorferi's flagellin, binds to heat shock protein 60 (HSP60) within live neuroblastoma cells: a potential role for HSP60 in peptide hormone signaling and in an autoimmune pathogenesis of the neuropathy of Lyme disease.

Heat Shock Protein 60 Autoimmunity in Lyme Disease