TUTKIMUS: IFN GAMMA BORRELIOOSISSA

[Bb]

Lähettäjä: Soijuv Lähetetty: 11.5.2004 13:44

Suomalainenkin tutkimusryhmä on todennut kohonneet gamma interferoni -arvot borrelioosia sairastavilla. Tutkimus vahvisti aikaisempia tutkimuksia joiden mukaan borrelioosia sairastavilla esiintyy Th1-tyypin sytokiinien (esim. gamma interferoni) aktivoitumista.


INFECTION AND IMMUNITY, Sept. 1996, p. 3620?3623 Vol. 64, No. 9

Decreased Interleukin-4 and Increased Gamma Interferon Production by Peripheral Blood Mononuclear Cells of Patients with Lyme Borreliosis

JARMO OKSI,1,2,3* JOHANNES SAVOLAINEN,4,5 JE´RO?ME PE`NE,5 JEAN BOUSQUET,5

PEKKA LAIPPALA,6 AND MATTI K. VILJANEN3,7

Spontaneous and Borrelia burgdorferi-stimulated proliferation of peripheral blood mononuclear cells (PBMCs) and their interleukin-4 (IL-4), gamma interferon (IFN-g), and NO production were measured in 36 patients with second- or third-stage Lyme borreliosis (LB) and 11 control subjects. Spontaneous proliferation of PBMCs was significantly higher (P 5 0.0003) in the LB patients than in the control subjects. Spontaneous production of IL-4 was significantly lower in patients than in control subjects (P 5 0.0007), but spontaneous production of IFN-g was slightly higher in patients. The proliferative response of PBMCs to stimulation with B. burgdorferi was significantly higher (P 5 0.01) in patients. The B. burgdorferi-induced production of IFN-g (P 5 0.002) was also significantly higher in patients. The spontaneous and B. burgdorferi-induced production of NO showed no significant difference between patients and control subjects.

These findings indicate that the activation of PBMCs in patients with late LB is enhanced in vivo. Furthermore, the production of IL-4 is effectively suppressed spontaneously, whereas the production of IFN-g by PBMCs is slightly increased spontaneously and significantly enhanced during stimulation with B. burgdorferi in vitro. The "spontaneous" or disease-induced alterations in cytokine levels of patients, in this case suppression of a Th2-type cytokine production and activation of a Th1-type cytokine production, may contribute to the pathogenesis of LB.

Lyme borreliosis (LB) is a multisystem disease with a strong tendency to chronicity. The severity of its symptoms has been associated with spirochete burdens in experimentally infected animals (31). However, it is likely that indirect mechanisms are partly responsible for the symptoms (11). The inciting pathogen, Borrelia burgdorferi, persisting in tissues, may cause continuous activation of lymphocytes and production of cytokines (14). The effects of tissue and circulating cytokines may explain many of the symptoms and inflammatory reactions of LB (14, 15, 25).

Previous studies have shown that Lyme disease patients have elevated concentrations of interleukin-1 (IL-1), IL-6, and tumor necrosis factor alpha in the blood (3, 7, 20).

T-cell clones derived from patients with chronic LB and T cells from animals experimentally infected with B. burgdorferi have been found to exhibit the Th1 phenotype exclusively; i.e., they produce gamma interferon (IFN-g) (32). Interestingly, the development of clinical arthritis seems to be associated with the production of Th1-type cytokines (IFN-g) whereas resistance to the development of overt arthritis seems to be associated with the production of Th2-type cytokines (IL-4) in experimentally infected mice (18 ). CD41 Th2 cells elicited by immunization also seem to protect mice from experimental borrelia infection (24). One study found striking differences in mouse spleen cell production of cytokines in vitro between disease-susceptible and -resistant mice, indicating the importance of IL-4 in early control of spirochete growth. In vivo studies on these experimentally infected mice further confirmed the above finding. Furthermore, the results indicated that IFN-g may inhibit the early control of spirochete growth in susceptible mice (13).

IFN-g can also be linked to tissue damage via NO. IFN-g induces intensive NO production by macrophages incubated with minute amounts of outer surface protein A (OspA) of B. burgdorferi (29). Although NO has potential antimicrobial properties, it may also be detrimental to the host (17).

We investigated spontaneous and B. burgdorferi-stimulated lymphocyte proliferation and production of IL-4, IFN-g, and NO by peripheral blood mononuclear cells (PBMCs) in 36 patients with second- or third-stage LB and in 11 control subjects.

MATERIALS AND METHODS

Patients and healthy controls. The mean age of the patients, 18 women and 18 men, was 44.2 years (range, 4 to 77 years). The mean age of the control subjects, seven women and four men, was 32.5 years (range, 25 to 39 years). All patients were suffering from second- or third-stage LB, diagnosed according to Centers for Disease Control and Prevention criteria (23). Of the 36 patients, 30 had musculoskeletal manifestations of LB (18 had arthritis, 1 had myositis, and 11 had arthralgia); 19 had neurologic manifestations (1 had encephalitis, 3 had leukoencephalitis, 3 had facial palsies, 3 had meningitis, 1 had radiculoneuritis, 1 had epilepsy and cerebral vasculitis, 5 had severe dizziness, 1 had optic neuritis, 3 had neuritis or neuropathy, 2 had encephalopathy, 1 had transient hemiparesis, 1 had diplopia, and 1 had tinnitus); 20 had multisystem disease (two or more organ systems involved); 33 had serum antibodies against B. burgdorferi as measured by enzyme-linked immunosorbent assay (ELISA) with whole sonicated bacteria as the antigen; and 24 had DNA of B. burgdorferi in their plasma, cerebrospinal fluid, or synovial fluid as detected by PCR with primers for a chromosomal gene encoding the flagellin protein (22). Immunoglobulin M and G antibodies against sonicated B. burgdorferi were measured by an in-house ELISA (27). Seropositivity was determined by comparing antibody results for test serum samples with those for samples from 110 healthy controls. The cutoff value for weakly positive results was the mean plus 2 standard deviations of results from the controls. The three seronegative patients were all PCR positive.