Leonard H. Sigal

A vaccine consisting of recombinant Borrelia burgdorferi outer-surface protein A to prevent lyme disease

BACKGROUND Lyme disease is a multisystem inflammatory disease caused by infection with the tick-borne spirochete Borrelia burgdorferi and is the most common vector-borne infection in the United States. We assessed the efficacy of a recombinant vaccine consisting of outer-surface protein A (OspA) without adjuvant in subjects at risk for Lyme disease. METHODS For this double-blind trial, 10,305 subjects 18 years of age or older were recruited at 14 sites in areas of the United States where Lyme disease was endemic; the subjects were randomly assigned to receive either placebo (5149 subjects) or 30 microg of OspA vaccine (5156 subjects). The first two injections were administered 1 month apart, and 7515 subjects also received a booster dose at 12 months. The subjects were observed for two seasons during which the risk of transmission of Lyme disease was high. The primary end point was the number of new clinically and serologically confirmed cases of Lyme disease. RESULTS The efficacy of the vaccine was 68 percent in the first year of the study in the entire population and 92 percent in the second year among the 3745 subjects who received the third injection. The vaccine was well tolerated. There was a higher incidence of mild, self-limited local and systemic reactions in the vaccine group, but only during the seven days after vaccination. There was no significant increase in the frequency of arthritis or neurologic events in vaccine recipients. CONCLUSIONS In this study, OspA vaccine was safe and effective in the prevention of Lyme disease.

Coexistent minocycline-induced systemic lupuserythematosus and autoimmune hepatitis

OBJECTIVES This study was performed to raise awareness among rheumatologists about two autoimmune disorders associated with long-term minocycline therapy that can coexist in the same patient. We provide an update on the occurrence of these disorders, their main characteristics, and the current knowledge of potential pathogenic mechanisms. METHODS We searched the medical literature in English indexed in MEDLINE from 1966 through April 1998 for the term minocycline combined with each of the following: autoimmune hepatitis (AIH), chronic hepatitis, lupus, systemic lupus erythematosus (SLE), anti-myeloperoxidase (anti-MPO), arthritis, vasculitis, and toxicity. We also reviewed relevant references cited in the articles our search uncovered. RESULTS We identified over 60 minocycline-induced cases of SLE and 24 cases of minocycline-induced AIH. Both autoimmune disorders coexisted in the same patient in 12 cases reported in the literature and in one case seen at our clinic. These 13 patients were characterized by symmetrical polyarthralgias/polyarthritis, elevated liver enzymes, and positive antinuclear antibodies (ANA); they also were generally anti-histone-negative, and only two patients had perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA). After withdrawal of minocycline, their symptoms resolved, and abnormal laboratory results normalized or markedly improved. CONCLUSIONS Although data on the actual prevalence of autoimmune disorders induced by minocycline are not available, numerous case reports or small series deal with such disorders. Probable pathogenic mechanisms for each of these conditions are discussed.

Use of Serum Immune Complexes in a New Test That Accurately Confirms Early Lyme Disease and Active Infection with Borrelia burgdorferi

ABSTRACT The present recommendation for serologic confirmation of Lyme disease (LD) calls for immunoblotting in support of positive or equivocal ELISA. Borrelia burgdorferi releases large quantities of proteins, suggesting that specific antibodies in serum might be trapped in immune complexes (ICs), rendering the antibodies undetectable by standard assays using unmodified serum. Production of ICs requires ongoing antigen production, so persistence of IC might be a marker of ongoing or persisting infection. We developed an immunoglobulin M (IgM) capture assay (EMIBA) measuring IC-derived IgM antibodies and tested it using three well-defined LD populations (from an academic LD referral center, a well-described Centers for Disease Control and Prevention (CDC) serum bank, and a group of erythema migrans patients from whose skin lesions B. burgdorferi was grown) and controls (non-Lyme arthritis inflammatory joint disease, syphilis, multiple sclerosis, and nondisease subjects from a region where LD is endemic, perhaps the most relevant comparison group of all). Previous studies demonstrated that specific antigen-antibody complexes in the sera of patients with LD could be precipitated by polyethylene glycol and could then be disrupted with maintenance of the immunoreactivity of the released antibodies, that specific anti-B. burgdorferi IgM was concentrated in ICs, and that occasionally IgM to specific B. burgdorferi antigens was found in the IC but not in unprocessed serum. EMIBA compared favorably with commercial and CDC flagellin-enhanced enzyme-linked immunosorbent assays and other assays in confirming the diagnosis of LD. EMIBA confirmed early B. burgdorferi infection more accurately than the comparator assays. In addition, EMIBA more accurately differentiated seropositivity in patients with active ongoing infection from seroreactivity persisting long after clinically successful antibiotic therapy; i.e., EMIBA identified seroreactivity indicating a clinical circumstance requiring antibiotic therapy. Thus, EMIBA is a promising new assay for accurate serologic confirmation of early and/or active LD.

Stress and psychosocial factors: effects on primary cellular immune response

Life stress is associated with decreases in some immune functions, but little is known about the effect of stress on immune response to active immunization. We examined the relationships between stressful events, psychosocial, and biologic factors and primary immune response to a novel antigen—keyhold limpet hemocyanin (KLH). Lymphocyte proliferation (LP) was measured prior to immunization and 3 and 8 weeks following KLH immunization. At 3 weeks, LP was significantly lower in subjects reporting more “bad” stress and those experiencing more psychological distress, while “good” stress and social support tended to be associated with higher LP. There was a trend toward the more stressed subjects having lower baseline, but higher 8-week, LP responses. The model that best fits these data suggests that psychosocial processes mediate the relationship between stressful events and primary immune response, while biologic factors, such as recent weight gain, show direct independent effects on immune response.

Molecular mimicry in Lyme disease: monoclonal antibody H9724 to B. burgdorferi flagellin specifically detects chaperonin-HSP60.

A monoclonal antibody (H9724), specific for the 41-kDa flagellar protein of the Lyme disease pathogen Borrelia burgdorferi, cross-reacts with human axons and detects one major protein in human neuroblastoma cell extracts. The homologous cross-reacting protein has now been isolated from calf adrenal and identified as chaperonin-HSP60 by N-terminal sequencing.

Autoimmune hepatitis associated with autoimmune hemolytic anemia and anticardiolipin antibody syndrome

Autoimmune hepatitis (AIH) is a disorder characterized by continuing hepatocellular necrosis and inflammation, usually with fibrosis, which tends to progress to cirrhosis and liver failure. The diagnosis of AIH depends on the exclusion of other causes of chronic hepatitis and the presence of an autoimmune response, namely anti-smooth muscle antibodies (ASMA), anti-nuclear antibodies (ANA), antibodies to liver–kidney microsomes (anti-LKM), antibodies to soluble liver antigen (anti-SLA), elevated aminotransferases, hypergammaglobulinemia and a response to immunosupressive therapy (1). Several autoimmune disorders, such as thyroiditis, rheumatoid arthritis, autoimmune hemolytic anemia, ulcerative colitis, proliferative glomerulonephritis, juvenile diabetes mellitus, and Sjogren’s syndrome, occur with increased frequency in patients with AIH and in their relatives (2). There are a few reports of a possible association between anti-phospholipid antibodies and AIH in the literature (3–6). We report a case of AIH associated with autoimmune hemolytic anemia, autoimmune thrombocytopenia, anti-phospholipid antibody syndrome, and sickle cell trait. CASE REPORT

Multi-well ELISA based on independent peptide antigens for antibody capture Application to Lyme disease serodiagnosis

Novel procedures for the use of peptides as antibody-capture reagents in the ELISA format have been investigated. Epitope sequences from known immunodominant antigens of Borrelia burgdorferi were selected by screening peptide libraries with sera from patients with Lyme disease. Several epitope peptides were synthesized and immobilized, separately, on the ELISA plate as haptens on bovine serum albumin. Based on a comparative analysis of serum samples, it appears that peptide antigens can be used as effectively as a whole cell lysate to discriminate between Lyme disease and non-Lyme disease sera, thus avoiding dependence on bacterial sonicates which vary from passage to passage. Further improvements in epitope design for enhancement of accuracy in serodiagnosis are discussed.

Immunopathogenesis of Lyme borreliosis

Abstract The clinical entity known as Lyme disease or Lyme borreliosis is caused by infection with Borrelia burgdorferi (and other recently described Borrelia species, whose differences from B. burgdorferi are currently being defined). It is, however, far from clear how this organism causes multisystem inflammatory damage. 1 Recent studies suggest that persistence of the organism may be implicated in chronic tissue damage, for example, chronic cardiomyopathy. 2–4 In the absence of toxin formation or invasive behavior by the organism, 5 the search for pathogenetic mechanisms has focused on the immunologic reactivity elicited by B. burgdorferi ; of note is the fact that in severe combined immune deficiency (scid) mice, tissue damage develops even in the absence of an intact immune system. 6 This article is a review of the in vitro and in vivo immunologic responses to B. burgdorferi that have been identified and speculation about how these may then cause tissue damage or dysfunction. It deals with three questions: 1.1. What immunologic responses does B. burgdorferi elicit in human or animal hosts? 2.2. What in B. burgdorferi elicits these changes? 3.3. How might these changes elicit tissue damage/cause disease? The ability of B. burgdorferi to elicit antigen-specific and nonspecific responses has been reviewed previously. 7,8 Antigen-specific T-cell 9,10 and humoral 11 reactivities have been used for diagnostic purposes. The immunologic changes elicited by B. burgdorferi are summarized by broad category in Table 1. These mechanisms, activated by live or dead organisms, can then cause chronic inflammation and tissue damage (Table 2) in a number of ways, summarized in this review. It has been suggested that specific immune responses may be implicated in the pathogenesis of certain aspects of the disease. Recent studies have shown differences in antigenic properties of North American and European strains of B. burgdorferi and suggested that these differences might be related to the different clinical features of Lyme disease (borreliosis) on the two continents. 12,13 Worthy of mention, however, is the fact that nonimmune mechanisms may be active in the pathogenesis of tissue dysfunction in Lyme disease; a recent fascinating study documents that a degradation component of tryptophan, produced by lipopolysaccharide-induced mononuclear cells, can diffuse across the blood-brain barrier and cause brain dysfunction (encephalopathy) in the absence of inflammation (encephalitis). Thus, patients may have brain dysfunction without having a central nervous system Borrelia infection. 14

Basic science for the clinician 58: IgG subclasses.

In evolutionary terms, IgG is the most recent addition to the human humoral immune response, the most recent of the 5 isotypes (classes). The IgG 4 subclasses and their multiple receptors, each with a unique structure and functions, speak to their broad repertoire of often overlapping functions. The IgG subclasses differ only slightly in structure, but therein lies their unique qualities. Focusing solely on the clinical niches filled by each and the clinical correlations thereof allows one to clearly see nature in its abhorrence of, and skill in filling, vacuums. One of the IgG subclasses, IgG4, the least in serum concentration, has recently become the topic of intense interest, as the linkage of certain diseases with IgG4 becomes apparent. As this association is studied, the molecular biology at the root of these diseases becomes the predominant cytokines explaining the pattern of histopathology.

N-Methyl-D-Aspartate Receptor-Mediated Chronic Pain: New Approaches to Fibromyalgia Syndrome Etiology and Therapy

Objectives: Fibromyalgia syndrome [FMS], a poorly understood form of chronic pain, is under-diagnosed and under-treated. It is possible that stress-induced disturbances of endocrine and neurological systems underlie the ultimate expression of FMS. One of these systems, involving the N-Methyl-D-Aspartate [NMDA] receptor, is implicated in FMS as it is in other chronic pain conditions. Therefore, the objective of this review is to provide evidence for targeting the NMDA receptor for FMS pharmacotherapy and discuss its significance to FMS pain. Findings: Major barriers to effective management of FMS pain are the fact that there are no discrete objectifiable physical findings, psychological stress is often thought to be the sole explanation, and the pathophysiology of FMS pain remains unclear. Yet, an impressive body of evidence suggests that FMS pain is likely due to central sensitization. Given its role in central pain perception and processing, the NMDA receptor represents a possible lynchpin in the pathogenesis of chronic pain in FMS. Conclusions: We propose that the very centrality of NMDA receptors in chronic pain makes them an ideal target for pharmacotherapy in FMS. Reports of recent clinical trials using newer low-affinity NMDA receptor antagonists have shown analgesic affects in chronic pain states other than FMS. These new compounds represent novel avenues of research into the management of chronic pain.