Lyme-borreliosis and inflammation

Borrelia induce a very specific immune response in the organism, which is apparently also limited in time and depends on the temporal phase of the infection.

In stage 1, erythema migrans, biopsies from the first days of infection show papillary skin edema and a mixed infiltrate consisting mainly of T cells, dendritic cells and monocytes or macrophages (Duray PH 1989). Cytokine expression at this stage is predominantly proinflammatory and includes elevated levels of tumor necrosis factor (TNF), interleukin-2, interleukin-6 and type I interferons (INF-alfa and IFN-beta).

Role of neutrophil granulocytes: It is known from animal and human studies that neutrophil granulocytes can kill B. burgdorferi very effectively. Apparently, neutrophil granulocytes are only present in a very early phase of the infection. As the early infection progresses beyond 24 hours, they are no longer present, while T cells, dendritic cells and monocytes continue to exist (Müllegger RR et al. 2000). Interestingly, tick saliva inhibits the function of neutrophils and can thus support the establishment of a B. burgdorferi infection. The inefficient neutrophil response is probably one reason why B. burgdorferi can effectively evade elimination. The infection is effectively established in the mammalian host. In animals expressing artificially elevated levels of a neutrophil-attracting chemokine, B. burgdorferi is rapidly cleared after inoculation into the dermis. This suggests that the absence of neutrophil granulocytes is important for the establishment of infection (Xu Q et al. 2007).

Complement: Complement also plays an early role in controlling infection, probably by enhancing phagocytosis and opsonization via the classical pathway. In early Lyme disease, as the erythema migrans lesions progress over days, dense perivascular and interstitial infiltrates develop. They consist of lymphocytes, plasma cells and occasionally mast cells. The anti-inflammatory cytokine interleukin-10 is found abundantly in these lesions (Sjöwall J et al. 2011). In animals with experimental IL-10 deficiency, there is increased inflammation and lower numbers of B. burgdorferi in the tissue. This indicates that although IL-10 leads to less inflammation and tissue damage, it enables B. burgdorferi to evade the immune system. The diacylglycerol glycolipid in the outer membrane of the spirochetes can directly activate NKT cells, which play an important role in controlling infection and enhancing phagocytosis (Kinjo Y et al.2006).

Complement resistance: Apparently, the mechanism of complement resistance of B. burgdorferi sensu stricto depends on the expression of several external surface proteins, the CRASPs (acronym for "complement regulator-acquiring surface protein" - see Borrelia antigens below). CRAPs can bind to host factor H, factor H-like protein and factor H-related proteins, which prevents complement-mediated killing of the bacteria in vitro.

Borrelia antigens: Much of the initial inflammatory response of the infected host appears to be mediated by "pathogen-associated molecular patterns" (PAMPs) recognized by pattern recognition receptors such as Toll-like receptors (TLRs) and cytosolic nucleotide-binding oligomerization domain-containing protein(NOD)-like receptors.

Different TLRs can recognize different PAMPs of B. burgdorferi, including various lipoproteins (recognized by TLR1 and TLR2), flagellin (recognized by TLR5), Borrelia RNA (recognized by TLR7 and TLR8) and CpG sites in DNA (recognized by TLR9- Note: CpG dinucleotides in DNA consist of the nucleobase sequence of cytosine and guanine. The 'p' in the CpG notation refers to the phosphodiester bond between cytosine and guanine/Petzke MM et al. 2009).

However, the response to B. burgdorferi lipoproteins appears to be the main stimulus that triggers the induction of host enzymes. This enzymatic digestion of extracellular matrix proteins allows the bacteria to more easily invade the tissue and induce inflammatory cytokines, which ultimately induces the inflammatory pattern of Lyme borreliosis. Note: In human Lyme arthritis, a polymorphism in TLR1 (leading to decreased expression of TLR1) is associated with increased levels of proinflammatory cytokines and persistent arthritis after antibiotic therapy (Strle K et al. 2012).

As the pathogen spreads from the original site of inoculation, the pattern of inflammatory cell recruitment, cytokine release and the nature of the inflammatory response continue at the sites to which the bacteria have spread. This affects the heart, joints and nervous system. All affected tissues show uniform infiltrates of mononuclear cells, particularly CD4+ and CD8+ T cells, and vascular abnormalities, suggesting that the spirochaetes were localized in or around the blood vessels (Duray PH (1987).

In animal models, differences in inflammatory infiltrates have been observed at different sites of infection and at different stages of the disease. For example, macrophages are abundant in cardiac lesions, whereas B cells and plasma cells are abundant in synovial lesions. In stage 3, synovial lesions in patients with antibiotic-refractory Lyme arthritis show synovial cell hypertrophy, vascular proliferation and sometimes obliterative microvascular lesions, in addition to mononuclear cell infiltrates consisting primarily of CD4+ and CD8+ T cells and macrophages, often with large numbers of plasma cells.

B cells are crucial for controlling the infection in all phases of Lyme disease infection. In the spleen, marginal zone B cells produce antibodies against T cell-independent antigens and are a source of B. burgdorferi-specific IgM antibodies in stage 1 disease (Oliver AM et al. 1997). The subsequent development of B. burgdorferi-specific IgG antibodies correlates with a detectable reduction in spirochete numbers in mice. Passively administered IgG antibodies can prevent the establishment of an infection in animal models. Within a few weeks to months, innate and adaptive immune mechanisms can reduce the bacterial count in immunocompetent individuals to such an extent that the systemic symptoms of Lyme borreliosis are reduced even without antibiotic treatment.

Borrelia and latency: In untreated patients, however, Borrelia can survive for several years in local niches, which in some cases can lead to persistent symptoms. In humans, however, all inflammatory manifestations of the disease, with the exception of acrodermatitis chronica atrophicans, eventually resolve without antibiotic therapy. Wild B. burgdorferi reservoirs, such as mice, do not develop infection-related pathology despite lifelong persistence of the bacteria. This finding indicates that their immune system has evolved to "tolerate" the presence of the organism. This is also due to the fact that the bacteria do not produce toxins or degradative factors and therefore pose less of a threat to the organism than the continued activation of the immune system caused by their presence.

Erythema migrans (E.m.): In Europe, s.l. erythema migrans caused by B. burgdorferi spreads more slowly than in the United States, and is usually not accompanied by other clinical symptoms. Although B. garinii infection also begins as a solitary skin lesion in most cases, itching and burning symptoms within the lesion are more common and local spread is more rapid than with B. afzelii or B. burgdorferi infection in Europe.

Lymphocytoma: A rare skin manifestation of early Lyme borreliosis in Europe is borrelial lymphocytoma, which is typically located on the earlobe in children and on the nipple in adults and is usually caused by B. afzelii infection (Mullegger RR 2004).

Acrodermatitis chronica atrophicans: In Europe, acrodermatitis chronica atrophicans - a slowly progressive lesion occurring mainly on the extensor sides (acres) of the extremities - is the most common late manifestation of Lyme borreliosis and, for unclear reasons, occurs more frequently in older women, while it is rare in children. Approximately 20% of patients with acrodermatitis chronica atrophicans have a history consistent with a previous spontaneously healed erythema migrans lesion, usually on an extremity where the acrodermatitis chronica atrophicans lesion developed 6 months to 8 years later. Acrodermatitis chronica atrophicans is primarily due to infection with B. afzelii, but can also be caused by B. garinii or European B. burgdorferi infections and begins with an inflammatory phase followed by an atrophic phase, sometimes with features. Peripheral neuropathy and joint involvement may occur at the skin sites affected by acrodermatitis chronica atrophicans.

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