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What effect does determining the HLA in the diagnosis and evaluation of the course of borreliosis have?

In approx. 10% of patients with Lyme borreliosis, joint problems persist for months and years despite adequate antibiotic therapy. Whenever such symptoms continue to persist, the question regarding the cause is always posed. Was the therapy insufficient or was the diagnosis wrong? The issue is supported by the fact that there is no certain laboratory diagnostic proof nor exclusion regarding borrelia due to the complex immune response. Lyme borreliosis is justifiably designated as the "great imitator" since the symptoms are very vague, which renders the clinical diagnosis considerably more difficult.

 

There is an association to HLA in the antibiotic-resistant progressive form of Lyme borreliosis.

Lyme arthritis sensitive and resistant to therapy differ in the cellular and humoral response to the "Outer surface protein A" (OspA) of the borrelia. In the process, various forms of the immune response play a decisive role, for example: autoimmune reactions which are associated with certain HLA types. It has been known for some time that people with HLA-DR2 or DR4 have a genetic predisposition for the development of an antibiotic-resistant Lyme borreliosis (relative risk is increased by a factor of 22!)

The latest studies display associations to certain HLA-DR subtypes.

In a current study in which the determination of HLA characteristics was performed using molecular-biological methods, STEERE et al. found significant associations between certain HLA-DR subtypes (DR*01:01, *15:01, *04:01 and *04:02) as well as the cellular and humoral mmune response to the OspA antigen of the borrelia. Apparently, OspA antigens release a cross reaction to endogenous structures when they are presented to the aforementioned HLA molecules in line with the immune response. This so-called "molecular mimicry" supports the inflammatory process through the autoimmune processes even when the pathogen itself has been eliminated. Originally, the sequence-homologous LFA-1 was postulated as an autoantigen. Its role in the pathogenesis of the autoimmune reaction, however, is currently undergoing controversial discussion again. It is assumed that various mechanisms associated with the so-called HLA molecules induce and support such an autoimmune reaction. The HLA molecules associated with the aforementioned borreliosis have an especially high affinity to OspA antigen fragments and present these long after the pathogen has been eliminated. Connected with this are high levels of pro-inflammatory cytokines (TNFa, INFg, etc.) in the affected tissues. The strong T-cell response to borrelia is connected to an inadequately high induction of inflammatory cytokines in appropriately genetically disposed patients and can thereby trigger an "autoimmune" response against endogenous structures. It has become apparent that carriers of two OspA-binding HLA-DR alleles are 11 times more susceptible to the risk of developing antibiotic-resistant Lyme borreliosis. This gene dosage effect underlines the fact that a close connection to certain HLA characteristics exists in the immunopathogenesis of therapy-resistant Lyme arthritis.

The association affects not only HLA alleles carrying shared epitopes.

Determining the DR subtypes in patients with antibiotic-resistant Lyme-borreliosis also resulted in the knowledge that the association does not contain itself to the so-called HLA-DR1/4 alleles carrying shared epitope, as previously assumed. The HLA allele DRB1*04:02 and *15:01 do not carry shared-epitope; however, they do bind OspA antigens. Patients who test positive for these alleles are also subject to an increased risk of developing a therapy-resistant progressive form.

Certain HLA alleles could be the cause of an absent formation of antibodies.

Besides the association to antibiotic-resistant Lyme-borreliosis, there is also the question of the HLA-DR association to seronegativity in proven borrelia infections (borrelia PCR and positive culture as the focus of new studies). In rare cases, patients do not develop specific antibodies against borrelia burgdorferi after a borreliosis infection. Wang & Hilton were able to show that almost 40% of these seronegative borreliosis patients tested positive for HLA-DR1.

The HLA-DR subtyping supports the diagnosis in unclear cases.

The diagnosis of borreliosis follows primarily on the basis of the anamnesis and the clinical symptoms, especially their chronological development. The laboratory diagnosis serves primarily to confirm the tentative diagnosis in this connection. However, the clinical picture is often ambiguous, especially in later stages of the disease which makes the diagnostic analysis much more difficult. The HLA-DR subtyping can be beneficial in defining therapy treatment in tentative borreliosis cases of a chronically persistent progressive form.

Summary of the study results to date

HLA association with antibiotic-resistant Lyme borreliosis:
DR1 (DRB1*01:01)
DR2 (DRB1*15:01)
DR4 (DRB1*04:01, 04:02)

HLA association with antibiotic-sensitive Lyme borreliosis:
DR8 (DRB1*08:01)
DR11 (DRB1*11:01, *11:04)
DR13 (DRB1*13:02)

HLA association in patients with a decreased formation of borrelia-specific antibodies in spite of an identified borrelia infection.
DR1 allele (DRB1*01:02, *01:01,*01:04, *01:05)

HLA association with strong seropositive borreliosis:
DR7 (DRB1*07:01, *07:03, *07:04)

Material and requirements

2 ml EDTA blood (blood count test tubes) are needed.
The laboratory requirement is: HLA-DR subtyping in borreliosis.

Transport of the blood sample to the laboratory is not time critical and can be done by mail. For genetic testing, we require the signed consent of the patient.For further questions please contact us by phone at 030 77001 220.

Payment

It is possible to bill patients who are covered by private medical insurance according to the German schedule of medical fees (GOÄ). The examination costs are €157,38.00 for self-pay patients (voluntary examination).

Literature

  • RA Kalish et al. (1993): Assiciation of Treatment-Resistant Chronic Lyme Arthritis with HLA-DR4 and Antibody Reactivity to OspA and OspB of Borrelia burgdorferi. Infektion and Immunity 61 (7).
  • AC Steere at al. (1990): Association of chronic Lyme-arthritis with HLA-DR4 and HLA-DR2 Alleles. N.Engl. J. Med. 323 (4).
  • AC Steere et al. (2006): Antibiotic-refractory Lyme arthritis is associated with HLA-DR molecules that bind a Borrelia burgdorferi peptide. JEM 203 (4).
  • P Wang & E Hilton (2001): Contribution of HLA Alleles in the Regulation of Antibody Production in Lyme Disease. Frontiers in Bioscience 6.