Lyme and Immune Complexes

Contents

• Borrelia burgdorferi-specific immune complexes in acute Lyme disease.
• Absence of Borrelia burgdorferi-specific immune complexes in chronic fatigue syndrome.
• The presence of antibodies to Borrelia burgdorferi associated with immunologic complexes in sera of foresters
• A one-step solid phase immunoassay for simultaneous detection of serum IgG and IgM antibodies to Borrelia burgdorferi.
• Immunoglobulin M capture assay for serologic confirmation of early Lyme disease: analysis of immune complexes with biotinylated Borrelia burgdorferi sonicate enhanced with flagellin peptide epitope.
• Use of serum immune complexes in a new test that accurately confirms early Lyme disease and active infection with Borrelia burgdorferi.
• Changes in granulocytic receptors for FcR IgG and CR with circulating immune complexes in patients with lyme borreliosis.
• Detection and preliminary characterization of circulating immune complexes in patients with Lyme disease.
• Lyme disease: laboratory diagnosis of infected and vaccinated symptomatic dogs.
• Immunologic reaction in patients with arthritis in the course of borreliosis with Lyme disease.
• Detection of Borrelia burgdorferi-specific antigen in antibody-negative cerebrospinal fluid in neurologic Lyme disease.
• Antibodies against whole sonicated Borrelia burgdorferi spirochetes, 41-kilodalton flagellin, and P39 protein in patients with PCR- or culture-proven late Lyme borreliosis.
• Diagnosis and clinical characteristics of ocular Lyme borreliosis
• Early and specific antibody response to OspA in Lyme Disease.
• Pathogenesis of immune-mediated neuropathies.
• Difficulties with Lyme serology.
• The prevalence and incidence of clinical and asymptomatic Lyme borreliosis in a population at risk.
• Cerebrospinal fluid immune complexes in patients exposed to Borrelia burgdorferi: detection of Borrelia-specific and -nonspecific complexes.
• Sequestration of antibody to Borrelia burgdorferi in immune complexes in seronegative Lyme disease.
• Acquired transient autoimmune reactions in Lyme arthritis: correlation between rheumatoid factor and disease activity.
• Immune complexes in leptospirosis.
• The pathogenesis of arthritis in Lyme disease: humoral immune responses and the role of intra-articular immune complexes.
• Lyme disease--a review of the literature.

1: JAMA 1999 Nov 24;282(20):1942-6

Borrelia burgdorferi-specific immune complexes in acute Lyme disease.

Schutzer SE, Coyle PK, Reid P, Holland B

CONTEXT: Diagnosis of infection with Borrelia burgdorferi, the cause of Lyme disease (LD), has been impeded by the lack of effective assays to detect active infection.

OBJECTIVE: To determine whether B. burgdorferi-specific immune complexes are detectable during active infection in LD.

DESIGN, SETTING, AND PATIENTS: Cross-sectional analysis of serum samples from 168 patients fulfilling
Centers for Disease Control and Prevention surveillance criteria for LD and 145 healthy and other disease controls conducted over 8 years. Tests were performed blinded.

MAIN OUTCOME MEASURE: Detection of B. burgdorferi immune complexes by enzyme-linked immunosorbent assay and Western blot.

RESULTS: The B. burgdorferi immune complexes were found in

• 25 of 26 patients with early seronegative erythema migrans (EM) LD;
• 105 of 107 patients with seropositive EM LD;
• 6 of 10 patients who were seronegative with culture-positive EM;
• 0 of 12 patients who were treated and recovered from LD; and
• 13 of 13 patients with neurologic LD without EM.
• Among 147 controls, B. burgdorferi immune complex was found in
• 0 of 50 healthy individuals;
• 0 of 40 patients with persistent fatigue;
• 0 of 7 individuals with frequent tick exposure; and
• 2 of 50 patients with other diseases.

PMID: 10580460, UI: 20046405

Absence of Borrelia burgdorferi-specific immune complexes in chronic fatigue syndrome.

Schutzer SE, Natelson BH

Chronic fatigue syndrome (CFS) and Lyme disease often share clinical features, especially fatigue, contributing to concern that Borrelia burgdorferi (Bb), the cause of Lyme disease, may underlie CFS symptoms. We examined

• 39 CFS patients and
• 40 healthy controls

PMID: 10522896, UI: 99450731
 
 

3: Wien Klin Wochenschr 1999 May 7;111(9):368-70

Ceftriaxone associated hemolysis.

Maraspin V, Lotric-Furlan S, Strle F

Department of Infectious Diseases, University Medical Centre Ljubljana,
Slovenia.

A 48-year-old immunocompetent women treated with ceftriaxone 2 g daily i.v. for
late Lyme borreliosis developed severe haemolytic anaemia. The patient had
previously received the same antibiotic two times without any side effects. The
first clinical signs began to appear on the 7th day of treatment. The
patient developed severe anaemia with a haemoglobin level of 45 mg/l on day 10;
thereafter she ceased to receive the antibiotic. The outcome was favourable. The
clinical course and serologic results suggest that severe anaemia was induced by
ceftriaxone and that drug adsorption as well as immune complex mechanisms were
involved in the pathogenesis.

PMID: 10407998, UI: 99336336

4: Med Dosw Mikrobiol 1998;50(1-2):97-103

[The presence of antibodies to Borrelia burgdorferi associated with immunologic complexes in sera of foresters].

Sobieszczanska BM, Nozka B, Milczarska J, Dobracka B, Dobracki W

Binding of antibodies specific to Borrelia burgdorferi in circulating immune complexes can lead to false negative results in serological tests. The aim of our study was to determine the presence of IgM antibodies to Borrelia burgdorferi bound in immune complexes in 52 sera of foresters the National Park in Karkonosze.

1. Free and bound in immune complexes IgM antibodies present in 6 (11.5%) examined sera.
2. In 24 (46.2%) seronegative sera after dissociation of immune complexes IgM antibodies to spirochaeta were  found.
3. The rest of the examined seronegative sera we failed to find IgM antibodies to Borrelia burgdorferi.

Publication Types:
Clinical trial

PMID: 9857619, UI: 99074946

5: J Immunol Methods 1998 Sep 1;218(1-2):9-17

A one-step solid phase immunoassay for simultaneous detection of serum IgG and IgM antibodies to Borrelia burgdorferi.

Schonau A, Stender H, Grauballe PC

A one-step immunoassay for simultaneous detection of serum IgG and IgM antibodies to Borrelia burgdorferi has been developed.

The assay is based on C1q, which binds to immune complexes containing IgG and/or IgM antibodies (1, 2).

Micro-beads pre-coated with antibodies to human C1q are mixed with human serum samples and fluorochrome-labelled B. burgdorferi flagellum antigen. In the presence of serum IgG and/or IgM antibodies to B. burgdorferi, fluorochrome-labelled antigen/antibody complexes are formed. These are then bound by serum C1q and are subsequently captured on the anti-C1q-coated beads.

The sample is analysed on a flow cytometer and the presence of fluorescent beads is, thus, indicative of a positive test result. In the present study the sensitivity and specificity of the assay are compared to those of the indirect IDEIA B. burgdorferi IgG and the mu-chain capture IDEIA B. burgdorferi IgM ELISAs for separate determination of IgG and IgM.

Detection using a flow cytometer can be performed without separation of the beads from the reaction mixture, which means that, in practice, the method is carried out as a one-step assay and it is, thus, very suitable for automation. Other advantages of this kind of assay includes an antibody/antigen reaction which occurs in solution and the potential of using the method for the detection of antibodies against several antigens from the same or different infectious agents (multi-parameter screening).

PMID: 9819119, UI: 99034428

Immunoglobulin M capture assay for serologic confirmation of early Lyme disease: analysis of immune complexes with biotinylated Borrelia burgdorferi sonicate enhanced with flagellin peptide epitope.

Brunner M, Stein S, Mitchell PD, Sigal LH

Abstract edited for enhanced legibility by J. Gruber

We previously reported on the efficacy of the enzyme-linked IgM capture immune complex (IC) biotinylated antigen assay (EMIBA) for the seroconfirmation of early Lyme disease and active infection with Borrelia burgdorferi (enhanced efficacy due to elimination of competition between immunglobulins and other components for binding sites on antigen, J. Gruber). In earlier work we identified non-cross-reacting epitopes of a number of B. burgdorferi proteins, including flagellin.

We now report on an improvement in the performance of EMIBA with the addition of a biotinylated form of a synthetic non-cross-reacting immunodominant flagellin peptide to the biotinylated B. burgdorferi B31 sonicate antigen source with the avidin-biotinylated peroxidase complex detection system used in our recently developed indirect IgM-capture immune complex-based assay (EMIBA).

As in our previous studies, we compared

• the enzyme-linked immunosorbent assay (ELISA) reactivities of antibodies liberated from circulating ICs by EMIBA
• with IgM-capture ELISA reactivities of antibodies in unprocessed serum (i.e. ELISA and not EMIBA), the sample usually used in standard ELISAs and Western blot assays. (Those assays check for free antibodies in the serum, disregarding antibodies bound in ICs, J. Gruber).

1. The addition of the flagellin epitope enhanced the ELISA signal obtained with untreated sera from many Lyme disease patients but not from healthy controls.
2. In tests with both free antibodies and ICs, with or without the addition of the flagellin epitope to the sonicate, we found the most advantageous combination was IC as the source of antibodies and sonicate plus the flagellin epitope as the antigen.
3. In a blinded study of sera obtained from patients with early and later-phase Lyme disease, EMIBA with the enhanced antigenic preparation compared favorably with other serologic assays, especially for the confirmation of early disease.

PMID: 9542940, UI: 98201939

Use of serum immune complexes in a new test that accurately confirms early Lyme disease and active infection with Borrelia burgdorferi.

Brunner M, Sigal LH.

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

1. an academic LD referral center,
2. a well-described Centers for Disease Control and Prevention (CDC) serum bank, and
3. a group of erythema migrans patients from whose skin lesions B. burgdorferi was grown

1. non-Lyme arthritis inflammatory joint disease,
2. syphilis,
3. multiple sclerosis, and
4. nondisease subjects from a region where LD is endemic, perhaps the most relevant comparison group of all.

• 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.

1. compared favorably with commercial and CDC flagellin-enhanced enzyme-linked immunosorbent assays and other assays in confirming the diagnosis of LD.
2. confirmed early B. burgdorferi infection more accurately than the comparator assays.
3. [M]ore 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.

PMID: 11526153 [PubMed - indexed for MEDLINE]

7: Przegl Epidemiol 1997;51(4):451-5

[Changes in granulocytic receptors for FcR IgG and CR with circulating immune complexes in patients with lyme borreliosis].

[Article in Polish]

Izycka A, Jablonska E, Pancewicz S, Zajkowska J, Swierzbinska R, Kondrusik M, Izycki T

Zaklad Immunopatologii Akademii Medycznej w Bialymstoku.

This study aimed to estimate some PMN functions, involving phagocytic activity
in patients with Lyme borreliosis. Decreased percentage PMN with FcR and CR
receptors was observed. Increased immune complexes levels in the serum of
patients before, and their normalization after treatment were found. These
results indicate a depression of non-specific cellular response, which can
influence the general immune system in patients with Lyme borreliosis.

PMID: 9562795, UI: 98223888

Detection and preliminary characterization of circulating immune complexes in patients with Lyme disease.

Zhong W, Oschmann P, Wellensiek HJ

To investigate whether circulating immune complexes can be used as a disease marker for assessment of the activity of Lyme disease and for monitoring patients response to treatment, we tested 104 sera from patients with different stages of Lyme disease using the C1q enzyme-linked immunosorbent assay (ELISA) and a modified Raji cell test.
 

1. Among 62 sera of patients with clinically active disease
1. 27 sera (43.5%) reacted positively in the C1q-ELISA and
2. 21 sera (33.9%) positively in the Raji cell test.
2. In contrast, serum circulating immune complexes were found in less than 10% of 42 sera after antibiotic treatment.
3. Similar results were obtained by both tests in 35 cerebrospinal fluid samples from patients with neuroborreliosis.
4. Most importantly, dot blot analysis revealed the presence of both Borrelia burgdorferi-specific antigen(s) and host-derived components in the isolated immune complexes from serum samples of patients with active Lyme disease.

PMID: 9403844, UI: 98067621

Lyme disease: laboratory diagnosis of infected and vaccinated symptomatic dogs.

Jacobson RH; Chang YF; Shin SJ

Serological assays for detection of canine antibodies to the Lyme agent generally have been difficult to validate because an acceptable standard of comparison such as unequivocal proof of infection status has not been available. For practical and logistical reasons, it has not been possible to use culture of organism from infected animals, seroconversion in a large number of field dogs, or clinical criteria as the standard of comparison for validation of assays. Therefore, estimates of diagnostic sensitivity and specificity based on an appropriate gold standard have not been available. When it was discovered how to infect laboratory dogs via ticks infected with Borrelia burgdorferi, it was possible to define the kinetics and magnitude of the antibody response that might be expected in nature. ELISA and Western immunoblot data from experimental dogs were then compared and correlated with results of the same tests on dogs from endemic and nonendomic areas. Coupled with studies on cross-reactive antibodies elicited from other infectious agents or autoimmune phenomena, it was possible to account for interfering antibodies and to establish estimates of diagnostic sensitivity and specificity for the ELISA based on objective criteria. Such validated assays can predict, with a relatively high degree of proficiency, the infection and/or vaccinal status of animals. These assays have shown that some dogs, vaccinated with the commercially available whole-cell Lyme bacterins develop typical signs of Lyme disease but have no evidence of an underlying infection; antibody elicited only by the vaccine and not by infection is detectable in these animals. Western immunoblot can also confirm infection in animals of equivocal ELISA status if their bands have been evaluated for specificity of antibodies to B burgdorferi. Serology can be a very useful aid in the diagnosis of Lyme disease, but it requires that the assays used have been subjected to rigorous validation criteria. When that is not performed, an unacceptable level of false-positive and false-negative test results is virtually assured.

NLM PUBMED CIT. ID: 8942214 NLM CIT. ID: 97097649 

9: Przegl Epidemiol 1996;50(3):253-7

[Immunologic reaction in patients with arthritis in the course of borreliosis
with Lyme disease].

[Article in Polish]

Flisiak R, Wiercinska-Drapalo A, Prokopowicz D

Klinika Obserwacyjno-Zakazna Akademii Medycznej w Bialymstoku.

Cell mediated as well as humoral immune response was evaluated in 14 lyme
arthritis patients. Significant decrease of T cells percentage was observed in
comparison to normal values. It was related particularly to CD4+ subset and
resulted in significant decrease of CD4+/CD8+ ratio. Statistically significant
increase of B cells percentage was accompanied by elevated concentrations of
immunoglobulin M, complement components C3 and C4. Immunoglobulins A and G, as
well as circulating immune complexes remained on the normal level. These results
indicate suppression of cellular and activation of humoral immune response in
patients with Lyme arthritis.

PMID: 8927735, UI: 97027669

Detection of Borrelia burgdorferi-specific antigen in antibody-negative cerebrospinal fluid in neurologic Lyme disease.

Coyle PK; Schutzer SE; Deng Z; Krupp LB; Belman AL Benach JL; Luft BJ

OBJECTIVE:
To determine the potential of detection in CSF of specific Borrelia burgdorferi antigen, OspA, as a marker of infection in neurologic Lyme disease and compare this with the detection of antibody.

DESIGN:
CSF from 83 neurologic patients in an area highly endemic for Lyme disease was examined prospectively for

1. OspA by antigen capture ELISA and Western blot employing monoclonal antibodies, and for
2. B burgdorferi antibodies by ELISA.

 

 

• 7 of these 15 (47%) had otherwise normal routine CSF analyses.
• 6 of these 15 (40%) patients met strict CDC surveillance criteria for Lyme disease;
• 4 (27%) patients had seroconversion coincident with new neurologic problems; and
• 3 (20%) with characteristic syndromes for Lyme disease were seronegative, but had complexed antibody to B burgdorferi.
• The final 2 patients (13%) were seropositive and had unexplained neurologic problems not characteristic of Lyme disease.

NLM PUBMED CIT. ID: 7501150 NLM CIT. ID: 96063525

Antibodies against whole sonicated Borrelia burgdorferi spirochetes, 41-kilodalton flagellin, and P39 protein in patients with PCR- or culture-proven late Lyme borreliosis.

Oksi J; Uksila J; Marjamaki M; Nikoskelainen J Viljanen MK

The sensitivities and specificities of three enzyme-linked immunosorbent assays (ELISAs) for Borrelia burgdorferi antibodies were compared for 41 patients presenting with symptoms compatible with late Lyme borreliosis (LB) and 37 healthy controls. All subjects were living in southwestern Finland, where LB is endemic. Only patients with culture- or PCR-proven disease were enrolled in the study.

The antigens of the ELISAs consisted of

• sonicated spirochetes,
• 41-kDa flagellin, and
• recombinant P39 protein of B. burgdorferi.

1. 15 patients had strongly or moderately positive results in the serological assay(s),
2. 19 patients had only weakly positive or borderline antibody levels, and
3. the remaining 7 patients were seronegative by ELISA.

1. 78.0% with sonicate antigen,
2. 41.5% with 41-kDa flagellin, and
3. 14.6% with P39 protein.

1. 89.2 with sonicate antigen,
2. 86.5 with 41-kDa flagellin, and
3. 94.6% with P39 protein.

CONCLUSIONS:
These results show that antibodies to B. burgdorferi may be present in low levels or even absent in patients with culture- or PCR-proven late LB. Therefore, in addition to serological testing, the use of PCR and cultivation is recommended in the diagnosis of LB.

NLM PUBMED CIT. ID: 7494012 NLM CIT. ID: 96025135

Diagnosis and clinical characteristics of ocular Lyme borreliosis [see comments]

Karma A; Seppala I; Mikkila H; Kaakkola S; Viljanen M; Tarkkanen A

COMMENTS:
Comment in: Am J Ophthalmol 1995 Aug;120(2):263-4

PURPOSE:
To establish a diagnosis, in a group of patients we studied the characteristics of ocular Lyme borreliosis.

METHODS:
During a two-year period, 236 patients with prolonged external ocular inflammation, uveitis, retinitis, optic neuritis, or unexplained neuro-ophthalmic symptoms were examined for Lyme borreliosis. Antibodies to Borrelia burgdorferi were measured by indirect ELISA and western blot. Cerebrospinal fluid was also analyzed by polymerase chain reaction.

RESULTS:

1. Ocular Lyme borreliosis was diagnosed in 10 patients on the basis of medical history, clinical findings, and serologic test results.
2. Results of ELISA disclosed that 5 patients were seropositive,
3. 2 patients showed borderline reactivity, and
4. 3 patients were seronegative.
5. 4 of the 5 patients with borderline or negative results by ELISA had a positive result by western blot analysis.
6. In 1 seropositive patient, polymerase chain reaction verified a gene of B. burgdorferi endoflagellin from the vitreous and cerebrospinal fluid specimen.
7. In 5 of the s6x patients with known onset of the Borrelia infection, the ocular disorder appeared as a late manifestation.
8. Abnormalities of the posterior segment of the eye, such as
• vitreitis,
• retinal vasculitis,
• neuroretinitis,
• choroiditis, and
• optic neuropathy
were seen in 6 patients.
9. in 1 patient each were seen
• bilateral paralytic mydriasis,
• interstitial keratitis,
• episcleritis, and
• anterior uveitis

CONCLUSIONS:
Late-phase ocular Lyme borreliosis is probably underdiagnosed because of weak seropositivity or seronegativity in ELISA assays. Ocular borrelial manifestations show characteristics resembling those seen in syphilis.

NLM PUBMED CIT. ID: 7832219 NLM CIT. ID: 95133613

10: Lab Invest 1995 Feb;72(2):146-60

Chronic lyme disease in the rhesus monkey.

Roberts ED, Bohm RP Jr, Cogswell FB, Lanners HN, Lowrie RC Jr, Povinelli L,
Piesman J, Philipp MT

Department of Pathology, Tulane Regional Primate Research Center, Tulane
University Medical Center, Covington, Louisiana.

BACKGROUND: We have previously reported the clinical, pathologic, and
immunologic features of "early" Borrelia burgdorferi infection in rhesus monkeys
(3). We have now evaluated these features during the chronic phase of Lyme
disease in this animal model.

EXPERIMENTAL DESIGN: Clinical signs, and pathologic changes at the gross and microscopic levels, were investigated 6 months post-infection in several organ systems of five rhesus macaques (Macaca mulatta), which were infected with Borrelia burgdorferi by allowing infected Ixodes scapularis nymphal ticks to feed on them. A sixth animal was used as an
uninfected control. Borrelia antigens recognized by serum antibody were identified longitudinally by Western blot analysis, and C1q-binding immune complexes were quantified. Localization of the spirochete in the tissues was achieved by immunohistochemistry and in vitro culture. The species of spirocheta cultured was confirmed by the polymerase chain reaction.

RESULTS: Chronic arthritis was observed in five out of five animals. The knee and elbow joints were the most consistently affected. Articular cartilage necrosis and/or degenerative arthropathy were the most severe joint structural changes. Synovial cell hyperplasia and a mononuclear/lymphocyte infiltrate were commonly seen. Nerve lesions were also observed, including nerve sheath fibrosis and focal demyelinization of the spinal cord. Peripheral neuropathy was observed in five out of five animals and could be correlated in the most severely affected monkey with the presence of higher levels of circulating immune complexes. Differences in disease severity did not correlate with differences in the antigens recognized on Western blot analysis.

CONCLUSIONS: B. burgdorferi infection in rhesus macaques mirrors several aspects of both the early and chronic phases of the disease in humans. This animal model will facilitate the study of the pathogenesis of Lyme arthritis and neuroborreliosis.

Comments:
Comment in: Lab Invest 1995 Feb;72(2):127-30

PMID: 7853849, UI: 95156954
 
 

11: J Infect Dis 1994 Oct;170(4):890-3

Fc- and non-Fc-mediated phagocytosis of Borrelia burgdorferi by macrophages.

Montgomery RR, Nathanson MH, Malawista SE

Department of Internal Medicine, Yale University School of Medicine, New Haven,
Connecticut 06520.

The Fc receptor (FcR) for immunoglobulin has been assigned a major role in the
ingestion of Borrelia burgdorferi, the Lyme disease spirochete, by macrophages.
Yet macrophages readily take up and kill B. burgdorferi that have not been
opsonized. By use of doubly-labeled macrophages infected with spirochetes and
analyzed by confocal fluorescence microscopy, simultaneous localization of both
FcR and spirochetes (opsonized and unopsonized) was quantified. After infection
with unopsonized spirochetes, bacterial surface antigen and the FcR remained
distinct, confirming the expectation that unopsonized uptake of B. burgdorferi
is largely independent of the FcR. A similar lack of colocalization was seen
when opsonized spirochetes were ingested by macrophages whose FcRs were
sequestered by an immune complex-coated substrate. Furthermore, comparable
efficiency of uptake was observed whether or not the FcR was engaged.

PMID: 7930732, UI: 95016039

Early and specific antibody response to OspA in Lyme Disease.

Schutzer SE, Coyle PK, Dunn JJ, Luft BJ, Brunner M

Borrelia burgdorferi (Bb), the cause of Lyme disease, has appeared not to evoke a detectable specific antibody response in humans until long after infection.

This delayed response has been a biologic puzzle and has hampered early diagnosis.

• Antibody to the abundant organism-specific outer surface proteins, such as the 31-kD OspA, has rarely been detected less than 6 mo after infection.
• Antibody to a less organism-specific 41-kD flagellin protein, sharing common determinants with other bacteria and thus limiting its diagnostic potential, may appear after 4 to 6 wks.

1. biotin-avidin Western blots and
2. immune complex dissociation techniques.

1. Specific complexed antibody to whole Bb and recombinant OspA was detected in 10 of 11 of the EM patients compared to 0 of 20 endemic area controls.
2. IgM was the predominant isotype to OspA in these EM patients.
3. Free IgM to OspA was found in half the EM cases.
4. IgM to OspA was also detected in 10 of 10 European patients with EM who also had reactive T cells to recombinant OspA.

PMID: 8040289, UI: 94314934

13: Pediatr Res 1993 Jan;33(1 Suppl):S90-4

Pathogenesis of immune-mediated neuropathies.

Rostami AM

Department of Neurology, University of Pennsylvania School of Medicine,
Philadelphia 19104.

A variety of peripheral neuropathies are believed to be immune-mediated. Acute
inflammatory demyelinating polyneuropathy or Guillain-Barre syndrome (GBS) is
the prototype of these neuropathies. GBS is characterized by acute progressive
motor weakness of the extremities and of bulbar and facial musculature. Deep
tendon reflexes are reduced or absent, and sensory symptoms are mild.
Respiratory failure and autonomic dysfunction may be seen. The cerebrospinal
fluid shows increased protein and no or very few cells. The nerve conduction
velocity is slowed, and the pathology shows segmental demyelination with
mononuclear cell infiltration. Studies from man and experimental animals suggest
an immunologic basis for demyelination of the peripheral nerves in GBS, but the
mechanism is not well understood.

Experimental allergic neuritis, an animal
model of GBS, is induced in laboratory animals by immunization with myelin P2
protein, some peptides of P2 protein, and galactocerebroside. The animals
develop weakness and show electrophysiologic and pathologic features similar to
GBS. P2-reactive T cells and antigalactocerebroside antisera can adoptively
transfer experimental allergic neuritis. Various antibodies to peripheral nerve
myelin and circulating immune complexes have been found in patients with GBS.
The target antigen(s) for these antibodies are not well understood, but neutral
glycolipids cross-reactive with Forssman antigen and gangliosides are possible
candidates.

The mainstay of therapy is the management of the paralyzed patient.
Steroids are ineffective. Plasmapheresis, especially early in the course of the
disease, can shorten the duration of paralysis and intubation. Results from a
multicenter study in the Netherlands demonstrate the efficacy of high-dose
immune globulin therapy in GBS.

Publication Types:
Review
Review, tutorial

PMID: 8381954, UI: 93165407

Difficulties with Lyme serology.

Banyas GT

NLM PUBMED CIT. ID: 1583267 NLM CIT. ID: 92259900

J Infect Dis 1991 Feb;163(2):305-10

The prevalence and incidence of clinical and asymptomatic Lyme borreliosis in a population at risk.

Fahrer H; van der Linden SM; Sauvain MJ; Gern L; Zhioua E; Aeschlimann A

A past history of clinical Lyme borreliosis and the 6-month incidence of clinical and asymptomatic Lyme borreliosis was studied prospectively in a high-risk population. In the spring, blood samples were drawn from 950 Swiss orienteers, who also answered a questionnaire. IgG anti-Borrelia burgdorferi antibodies were detected by ELISA. Positive IgG antibodies were seen in 248 (26.1%), in contrast to 3.9%-6.0% in two groups of controls (n = 101). Of the orienteers, 1.9%-3.1% had a past history of definite or probable clinical Lyme borreliosis. Six months later a second blood sample was obtained from 755 participants, 558 (73.9%) of whom were seronegative initially; 45 (8.1%) had seroconverted from negative to positive. Only 1 (2.2%) developed clinical Lyme borreliosis. Among all participants, the 6-month incidence of clinical Lyme borreliosis was 0.8% (6/755) but was much higher (8.1%) for asymptomatic seroconversion (45/558). In conclusion, positive Lyme serology was common in Swiss orienteers, but clinical disease occurred infrequently.

NLM PUBMED CIT. ID: 1988513 NLM CIT. ID: 91108157

14: Ann Ital Med Int 1991 Oct-Dec;6(4 Pt 2):483-90

Collagenopathic cardiopathies.

Carcassi U, Passiu G

II Cattedra di Reumatologia, Universita degli Studi di Roma La Sapienza, Italy.

Collagenopathic cardiopathies are a subject of extreme etiologic, pathogenetic
and clinical interest. These disorders are associated with congenital or
acquired anomalies of the connective tissue and because of the diffusion and
nearly total distribution of this tissue, have a higher frequency than what has
been previously estimated. The collagenopathic cardiopathies, can be divided
into two main groups: one deriving from hereditary connective tissue diseases,
and the other from acquired connective tissue diseases. The first group has a
Mendelian type of transmission whereas the other appears to be secondary to
various kinds of stimuli (viral, immunologic etc.) although polygenic factors
are present. Of the first group we considered Marfan's syndrome, the
Ehlers-Danlos syndrome, osteogenesis imperfecta, pseudoxanthoma elasticum, cutis
laxa and the diseases of the fundamental substance with particular reference to
mucopolysaccharidosis type 1H (Hurler's syndrome). In all of these disorders a
specific metabolic disturbance is responsible for the cardiovascular damage
which is expressed, depending on the specific genetic component in a more or
less serious form. Among the acquired diseases of the connective tissue, we
examined rheumatoid arthritis, systemic lupus erythematosus,
polydermatomyositis, scleroderma; of the reactive arthritis, rheumatic fever; of
the seronegative forms, spondyloarthritis, ankylosing spondylitis and Reiter's
syndrome, mixed connective tissue disease and Lyme's disease. It must be
emphasized that all of these disorders share relatively common pathogenetic
characteristics which point to the importance of the presence of various types
of antigens, immune complexes and the significant role of some of the
histocompatibility antigens, as well as possible disturbances of cell-mediated
immunity.

PMID: 1840815, UI: 93002044
 
 

15: Cutis 1991 Apr;47(4):229-30, 232

Diagnosing Lyme disease: often simple, often difficult.

Schutzer SE, Schwartz RA

Department of Medicine, UMDNJ-New Jersey Medical School, Newark 07103.

Lyme disease has as its hallmark erythema migrans. However, it is only present
in about one half of the patients who contract this disease. In its absence, the
diagnosis of Lyme disease may be difficult. It depends upon a compatible history
of exposure and clinical signs and symptoms together with positive results of
serologic testing. Unfortunately, seronegativity for antibody to the pathogen
may occur both during the first six weeks of infection and be chronic due to the
reactive antibody being bound in immune complexes. The selective use of new
diagnostic tests may be required to confirm the diagnosis. These tests include
assays for antibody or antigen analysis of immune complex components, as well as
polymerase chain reactions.

Publication Types:
Review
Review, tutorial

PMID: 2070642, UI: 91300888

Cerebrospinal fluid immune complexes in patients exposed to Borrelia burgdorferi: detection of Borrelia-specific and -nonspecific complexes.

Coyle PK, Schutzer SE, Belman AL, Krupp LB, Golightly MG

We analyzed cerebrospinal fluid (CSF) from 32 patients with neurological symptoms and evidence of Borrelia burgdorferi infection

• (29 were seropositive as determined by enzyme-linked immunosorbent assay,
• 2 were cell-mediated immune positive, and
• 1 had been seropositive as shown by enzyme-linked immunosorbent assay 9 months previously).
• CSF immune complexes were found in 22 (69%) of 32 patients;
• in 18, there was sufficient sample to isolate immune complexes.
• By enzyme-linked immunosorbent assay, isolated immune complexes from 10 of these 18 patients contained antibody specific for B. burgdorferi antigens. The isotypes were IgG (n = 8), IgM (n = 3), and IgA (n = 2).
• By immunoblot, these antibodies were directed against B. burgdorferi 41-kDa antigen and occasionally against the 33- and 17-kDa antigens.
• Anti-B. burgdorferi IgM was present in patients with acute neurological symptoms, was predominantly complexed rather than free, and decreased with clinical recovery in the one serial study.
• 3 patients were nonreactive for free CSF antibodies, but had complexed antibodies to the organism.

PMID: 2285261, UI: 91136153

Sequestration of antibody to Borrelia burgdorferi in immune complexes in seronegative Lyme disease.

Schutzer SE, Coyle PK, Belman AL, Golightly MG, Drulle J

To find out whether apparent seronegativity in patients strongly suspected of having Lyme disease can be due to sequestration of antibodies in immune complexes, such complexes were isolated and tested for antibody to Borrelia
burgdorferi.
 

1. In a blinded analysis the antibody was detected
• in all 10 seronegative Lyme disease patients with erythema chronicum migrans (ECM),
• in none of 19 patients with other diseases, and
• in 4 of 12 seronegative patients who probably had Lyme disease but had no ECM.
2. These findings were confirmed by western blot, which also showed that immune complex dissociation liberated mainly antibody reactive to the 41 kD antigen and sometimes antibody to an approximate 30 kD antigen.
3. Complexed B burgdorferi antibody was also found in
• 21 of 22 (95%) of seropositive patients with active disease,
• 3 additional seronegative but cell mediated immune reactive patients, and
• 3 other seronegative patients who eventually became seropositive.

PMID: 1967770, UI: 90135740

Acquired transient autoimmune reactions in Lyme arthritis: correlation between rheumatoid factor and disease activity.

Goebel KM, Krause A, Neurath F

Department of Medicine, University Hospital, Marburg, West Germany.

Lyme spirochaetal disease (LSD) is a complex multisystem disorder which has been recognized as a separate entity due to its close geographic clustering of affected patients. The study aimed at evaluating the clinical and immunological features of LSD with chronic symptoms of meningoradiculitis, carditis and pauciarticular arthritis. Six patients with LSD and erosive arthritis who developed an increase of serum IgM rheumatoid factor (RF) which correlated with the inflammatory activity of the disease are described in detail. Besides raised IgG antibody titers to Borrelia burgdorferi (B. burgd.) antigen measured by ELISA technique, circulating immune complexes, antinuclear antibodies (ANA) and RF measured by laser nephelometric immunoassay were detected. Increased ANA and RF antibody rates suggest that LSD may closely be linked with transient autoimmune phenomena. Thus, in some cases, B. burgd. antigens might be able to produce a strong polyclonal B-cell stimulation, hence leading to an unspecific autoimmune reaction. But the question remains if transient unspecific autoimmune reactions actually take part in the pathogenesis of LSD.

PMID: 3238365, UI: 89186685
 
 

19: Med Clin North Am 1985 Jul;69(4):623-36

Clinical utility of assays for circulating immune complexes.

Endo L, Corman LC, Panush RS

Publication Types:
Review

PMID: 3903373, UI: 86039054

20: Infection 1985 May-Jun;13(3):156

Immune complexes in leptospirosis.

Galli M, Esposito R, Crocchiolo P, Chemotti M, Gasparro M, Dall'Aglio PP

Publication Types:
Letter

PMID: 4030109, UI: 85287599
 
 

21: Acta Paediatr Scand 1985 Jan;74(1):133-6

Lyme disease in a 12-year-old girl.

Sturfelt G, Cavell B

We report the case of a 12-year-old girl with erythema chronicum migrans,
aseptic meningitis and knee arthralgia. Rise of specific antibody titre against
an Ixodes ricinus spirochaete was demonstrated. Circulating immune complexes and
high levels of C1r-C1s-C1IA complexes indicating activation of the complement
system via the classical pathway were found. The clinical features and the
laboratory findings warranted a diagnosis of Lyme disease.

PMID: 3984718, UI: 85171163
 
 

22: Adv Clin Chem 1985;24:1-60

Immune complexes in man: detection and clinical significance.

McDougal JS, McDuffie FC

Publication Types:
Review

PMID: 2936066, UI: 86126364
 
 

23: J Infect Dis 1984 Oct;150(4):497-507

Interactions of phagocytes with the Lyme disease spirochete: role of the Fc
receptor.

Benach JL, Fleit HB, Habicht GS, Coleman JL, Bosler EM, Lane BP

The phagocytic capacity of murine and human mononuclear and polymorphonuclear
phagocytes (including peripheral blood monocytes and neutrophils), rabbit and
murine peritoneal exudate cells, and the murine macrophage cell line P388D1
against the Lyme disease spirochete was studied. All of these cells were capable
of phagocytosing the spirochete; phagocytosis was measured by the uptake of
radiolabeled spirochetes, the appearance of immunofluorescent bodies in
phagocytic cells, and electron microscopy. Both opsonized and nonopsonized
organisms were phagocytosed. The uptake of opsonized organisms by neutrophils
was blocked by a monoclonal antibody specific for the Fc receptor and by immune
complexes; these findings suggested that most phagocytosis is mediated by the Fc
receptor. Similarly, the uptake of opsonized organisms by human monocytes was
inhibited by human monomeric IgG1 and by immune complexes. These results
illustrate the role of immune phagocytosis of spirochetes in host defense
against Lyme disease.

PMID: 6386995, UI: 85031981

24: Yale J Biol Med 1984 Jul-Aug;57(4):589-93

The pathogenesis of arthritis in Lyme disease: humoral immune responses and the role of intra-articular immune complexes.

Hardin JA, Steere AC, Malawista SE

Circulating C1q binding material was found in nearly all patients at onset of erythema chronicum migrans, the skin lesion that marks the onset of infection with the causative spirochete. In patients with only subsequent arthritis this material tended to localize to joints where it gradually increased in concentrations with greater duration of joint inflammation. In joints, its concentration correlated positively with the number of synovial fluid polymorphonuclear leukocytes. Despite the prolonged presence of putative immune complexes, rheumatoid factors could not be demonstrated.

These observations suggest that phlogistic immune complexes based on spirochete antigens form locally within joints during chronic Lyme arthritis.

PMID: 6334939, UI: 85092791

25: Semin Arthritis Rheum 1984 Feb;13(3):229-34

Lyme disease--a review of the literature.

Williamson PK, Calabro JJ

• cryoglobulins containing IgM,
• Clq-reactive material, and
• depressed IgG and IgA levels)

Despite systemic clearing in some patients, the immune complexes localize to the joints where a chronic synovitis develops, similar to rheumatoid arthritis. Why the immune complexes localize to the joints is an enigma. It is tempting to postulate that this localization occurs because of an altered immune response in a genetically predisposed group. However, three of 10 patients with chronic arthritis did not have the B-cell alloantigen DRw2.

PMID: 6233699, UI: 84223994
 
 

26: Clin Exp Rheumatol 1983 Oct-Dec;1(4):327-32

Saturable, high-avidity monocyte receptors for monomeric IgG and Fc fragments
increase in SLE and lyme disease.

Hardin JA, Downs JT

We have devised an assay for quantifying high-avidity Fc receptors for monomeric
IgG on peripheral blood monocytes. In the development of a radiolabelled ligand
for the assay, we found that Fc fragments offer several advantages over 7S-IgG.
Compared to the latter ligand, the fragments interacted more cleanly with a
single high-avidity binding site, appeared to have easier access to this site,
and, since they showed no binding to Millipore filters, their use made possible
a wash procedure that was convenient and rapid, thus minimizing loss of
specifically bound ligand. Application of the assay to a study of ten normal
controls, five patients with SLE, and three patients with Lyme disease
demonstrated that normal monocytes bear approximately 10,000 high-avidity
binding sites per cell. In contrast, patient monocytes bore significantly more
Fc receptors; on average their cells had about 40,000 such sites per cell (P =
0.01) and sometimes as many as 100,000 sites per cell. Both normal and patient
monocytes bound IgG or Fc fragments with an apparent association constant (KA)
of approximately 10(8) M-1. The majority of patients with active SLE and Lyme
disease had serum C1q-binding material compatible with the presence of
circulating immune complexes. This study shows that these putative circulating
immune complexes do not necessarily lead to a reduction in the number of Fc
receptors on peripheral blood monocytes. Rather, the data suggest that in the
course of immune mediated diseases, either monocytes are activated in vivo to
express greater numbers of Fc receptors, or a subset of monocytes bearing more
Fc receptors is expanded.

PMID: 6241857, UI: 85177804
 
 

27: Hum Pathol 1983 Apr;14(4):343-9

Immune complex assays in rheumatic diseases.

Agnello V

A wide variety of antigen-nonspecific immune complex assays have been developed
in recent years for the detection and quantitation of immune complexes in
pathologic fluids. These assays detect complexed antibody regardless of the
antigen involved. Almost all of these assays use biologic reagents that may
react with substances other than complexed antibody. In addition, the assays do
not differentiate nonspecifically aggregated antibody from antigen-complexed
antibody. Hence, these assays are not absolute tests for immune complexes. On
the basis of studies using these assays, "immune complexes" have been detected
in a large number of rheumatic diseases. While these findings have been of
considerable investigative interest, thus far they have been of little practical
clinical utility. The detection of immune complexes has not been shown to be
essential in any clinical conditions but may be helpful in monitoring disease
activity in systemic lupus erythematosus (SLE) and may provide useful diagnostic
information in two rare syndromes, Lyme arthritis and SLE-related syndrome.

Publication Types:
Review

PMID: 6187658, UI: 83159380
 
 

28: Pediatr Infect Dis 1983 Jan-Feb;2(1):47-9

Lyme disease with neurologic abnormalities.

Darras BT, Annunziato D, Leggiadro RJ

PMID: 6220264, UI: 83169227
 
 

29: Nouv Presse Med 1982 Jan 9;11(1):39-41

[Lyme's disease. A clinical case observed in Western France].

[Article in French]

Mallecourt J, Landureau M, Wirth AM

The clinical story of a young woman with chronic erythema migrans followed by
polyradiculoneuritis and recurrent oligoarthritis is reported. The story
corresponds to the disease described by Steere et al. [7, 8, 9, 10] in 1976 and
known in the U.S.A. as "Lyme's disease". The condition is epidemic and occurs
during the summer. It begins with skin lesions characteristic of chronic
erythema migrans, which are consecutive to tick bite. This is followed, a few
days or weeks later, by neurological disorders (aseptic meningitis,
encephalitis, cranial nerve paralysis and/or polyradiculoneuritis), transient
and recurrent attacks or arthritis mostly in the larger joints and,
occasionally, conduction disorders in the heart. The course of the disease is
that of an inflammatory condition. The presence of immune complexes in the serum
and synovial fluid is suggestive of local and systemic immune reaction to a
hypothetically viral agent introduced by the tick bite. The fact that the
incidence of DR W2 antigen is greater in patients with severe lesions suggests
individual predisposition.

PMID: 7058122, UI: 82126736
 
 

30: Dtsch Med Wochenschr 1980 Dec 19;105(51):1779-81

[Erythema chronicum migrans with arthritis].

[Article in German]

Ackermann R, Runne U, Klenk W, Dienst C

In a 46-year-old woman arthritis developed in several large joints eight weeks
after the onset of erythema chronicum migrans. The joints of the leg were
swollen and painful. In addition there was painful involvement bilaterally of
knee, hip and elbow joints. Circulating immune complexes were demonstrated in
serum and the erythrocyte sedimentation rate was moderately increased. All other
laboratory and radiological tests were within normal limits. On symptomatic
treatment the arthritis regressed without sequelae within six weeks. The disease
is nosologically related to Lyme disease recently described in the North East of
the U.S.A. in which erythema chronicum migrans is followed by arthritis; here,
too, circulating immune complexes have been demonstrated.

PMID: 7439072, UI: 81066455
 
 

31: N Engl J Med 1979 Dec 20;301(25):1358-63

Immune complexes and the evolution of Lyme arthritis. Dissemination and
localization of abnormal C1q binding activity.

Hardin JA, Steere AC, Malawista SE

In a prospective study of 78 patients with Lyme arthritis, abnormal serum C1q
binding activity was present at the initial onset of erythema chronicum migrans
in nearly all cases. The abnormal binding persisted in patients with subsequent
nerve or heart involvement. In contrast, among those with only subsequent
arthritis, it usually disappeared within three months (P = 0.018). However, in
the synovial fluid of affected joints, abnormal binding was uniformly present,
and always to a greater extent than in the circulation. The abnormally reactive
material behaved like antigen-antibody complexes. It had a density of 19S or
greater, dissociated below pH 4.2, and lacked antiglobulin activity.
Cryoprecipitates containing immunoglobulin were good but insensitive predictors
of its presence, but immune complexes themselves did not seem primarily
responsible for cryoprecipitability. Thus, as judged by C1q binding, immune
complexes remain disseminated in certain patients with Lyme arthritis but
localize to joints in others.

PMID: 503166, UI: 80054658
 
 

32: J Clin Invest 1979 Mar;63(3):468-77

Circulating immune complexes in Lyme arthritis. Detection by the 125I-C1q
binding, C1q solid phase, and Raji cell assays.

Hardin JA, Walker LC, Steere AC, Trumble TC, Tung KS, Williams RC Jr, Ruddy S,
Malawista SE

PMID: 429566, UI: 79151567
 
 

33: Am Fam Physician 1978 Jan;17(1):161-6

Arthralgias and arthritis in viral infections.

Franklin EC

Arthritis and arthralgias are common in many viral infections. They are
particularly prominent with hepatitis B virus and rubella infection, where they
may be the major presenting symptom. "Lyme arthritis" is also associated with a
virus. Similar symptoms are occasionally seen with adenovirus, Coxsackie and
echovirus infection. Joint lesions are due to the deposition of immune complexes
and not direct viral infection. While the arthritis is usually transient and
self-limited, the physician must consider viral infections as etiologic agents
of arthralgias and arthritis.

PMID: 146421, UI: 78100292
 
 

34: Science 1977 Jun 3;196(4294):1121-2

Erythema chronicum migrans and Lyme arthritis: cryoimmunoglobulins and clinical
activity of skin and joints.

Steere AC, Hardin JA, Malawista SE

We report the presence of serum cryoimmunoglobulins in patients with attacks of
a newly described epidemic arthritis--Lyme arthritis--and in some patients with
a characteristic skin lesion--erythema chronicum migrans--that sometimes
precedes the onset of the arthritis. Seven patients who had cryoimmunoglobulins
at the time of the skin lesion have developed arthritis; four patients without
them have not. The cryoglobulins in patients with the skin lesion consisted
primarily of immunoglobulin M (IgM); those in patients with arthritis often
included both IgM and IgG. These findings support the hypothesis that a common
origin exists for the skin and joint lesions and suggest that circulating immune
complexes may have a pathogenetic role in Lyme arthritis.

PMID: 870973, UI: 77174694