Sitaattia lähteestä:
MMPs in Cerebrospinal Fluid of patients with Lyme neuroborreliosis.
Perides G, Charness
ME, Tanner L, Péter O, Satz N, Steere AC, Klempner MS. (1997)
Neurologic manifestations of Lyme disease include meningitis,
encephalopathy and cranial and peripheral neuropathy. There are no
sensitive markers for neuroborreliosis, and diagnosis is often based
on clinical presentation and cerebrospinal fluid (CSF) abnormalities,
including intrathecal antibody production- matrix metalloproteinase
(MMP) activity in CSF was compared in patients with
neuroborreliosis, patients with diverse neurological disorders, and
healthy controls. The CSF of 17 of 18 healthy subjects and 33 of 37
patients with neurologic symptoms and normal CSF and imaging studies
contained only MMP2.
The CSF of several patieants with neurologic
disorders contained MMP2, MMP9, and gelatinolytic activity at 130 and
250 kDa. The 150-kDa MMP was found without the 92-kDa MMP9 in the CSF
of 11 (79%) of 14 patients with neuroborreliosis and only 7 ( 6%) of
118 control patients (P under.001). This pattern of CSF gelatinase
activity may be a useful marker of Lyme disease.
Patients usually have cerebrospinal fluid (CSF) abnormalities,
incl. elevated total protein, intrathecal antibody production to B.
Burgdorferii, or a positive polymerase chain reaction (PCR) test for
spirochetal DNA. In addition, increased amounts of neurofilaments and
glial fibrillary acidic protein degradation products have been noted
in CSF. The polyneuropathy is usually accompanied by spinal radicular
pain or peripheral dysesthesias, and electromyography (EMG) often
shows a diffuse axonal polyneuropathy.
MATRIX METALLOPROTEINASES (MMPs) are enzymes that contain zinc
in their active center and require Ca2+ for proteolytic activity.
Several MMPs have been identified in the human brain, including
gelatinase A (MMP2), gelatinase B (MMP9), stromelysin (MMP3), and
collagenase (MMP1). Two additional bands with gelatinolytic activity
and electrophoretic mobility corresponding to 130 and 250 kDa have
been identified but not fully characterized. It hs been suggested
that the 130-kDa band is a complex of gelatinase B and tissue
inhibitor of metalloproteinase-1 (TIMP-1) or a dimer of the active
68.jDa form of gelatinase B.
Increased concentrations of MMPs have been identified in the
central nervous systems (CNS) of patients with Alzheimer´s disease,
brain injury, and brain tumors. MMPs have also been detected in the
CSF of patients with inflammatory diseases, amyotrophic lateral
sclerosis (ALS), and multiple sclerosis (MS).
We recentrly reported the presence of 130-kDa gelatinolytic activity
in the CSF of a patient with a documented Lyme
neuroborreliosis. Here we analyze the pattern of MMPs in the CSF
of patients with Lyme neuroborreliosis compared with healthy persons
and patients with other* neurologic diseases.
(Other *neurologic conditions were: 1) Alzheimers disease, 2)
Parkinsons´s disease, 3) multiple sclerosis, 4) HIV encephalopathy, some with viral meningitis, bacterial or fungal encephalopathy; 5)
metabolic encephalopathy, 6) lymphoproliferative disorders with
sepsis or encephalopathy, 7) primary brain tumors, (8) metastatic
tumors, 9) epidural haematoma, 10) subarachnoidal haematoma, 11)
subdural haematoma, 12) transverse myelitis, 13) Guillan-Barre´´
syndrome.
...
From results:
Human CSF gelatinase A is secreted in a latent form (72 kDa) and is
activated in vivo to a 64-kDa form by plasmin or other MMPs.
…
MMPs are expressed in virtually all tissues.
Expression of
MMPs is increased during physiological remodeling of tissues,
such as mammary gland involution, postpartum uterine muscle
contraction, and wound healing. Increased expression of MMPs also
occurs in several pathologic conditions, including arthritis and
malignant tumors.
In the CNS, increased MMP expression has been associated with
multiple sclerosis, inflammatory neurologic disorders, amyotrophic
lateral sclerosis, brain tumors, and Alzheimres disease. Gelatinases
A and B are expressed in microglia and astrocytes. Collagenase
(MMP1), matrilysin (MMP7), and stromelysin (MMP3) have been
identified in gliomas.
The major finding of this study was that CHF of 78% of patients
with Lyme neuroborreliosis contained a 130-kDa MMP without the 92-kDa
gelatinase B. This pattern was relatively specific, occurring in
only 6% of the CSF samples of 118 nonneurologic controls and
patients with diverse neurologic disorders. This pattern was not
observed in any of 11 patients with nonborrelial CNS infection. The
expression of the 130 kDa-MMP without the 92-kDa gelatinase B may
therefore be a useful laboratory marker for Lyme neuroborreliosis.
In most but not all patients, there was a correlation between CSF
pleocytosis and expression of gelatinase B, as noted previously,
whereas gelatinase A was constitutively expressed in all of our
patient groups. The CSF of persons without neurologic complaints
contained only gelatinase A, as judged by electrophoretic mobuility
and immunoblot analysis.
We characterized the gelatinolytic activity in the CSF of 100
patients with neurologic symptoms (38 neurologic controls and 62 with
documented neurological diseases). Our observation that the CSF of
patients with multiple sclerosis and no CSF pleocytosis
contained only gelatinase A and no other gelatinases agrees
with the finding of Gijbels et al.
In that study, gelatinase
B was found primarily in the CSF of those multiple sclerosis
patients with CSF pleocytosis, suggesting that gelatinase B
is produced by white blood cells. The presence of gelatinase B in
the CSF of patients with brain tumors and no pleocytosis
suggests that this MMP may also derive from neoplastic and
glial cells.
The CSF of some patients with presumed Alzheimer´s dementia
contained only gelatinase A. This was surprising, since it was
raported, and we have confirmed, that the brain parenchyma of
patients with Alzheimers´s disease contain increased amounts of both
gelatinase B and the 130-kDa MMP .
The mechanismi underlying the expression of the 130-kDa MMP in
Lyme neuroborreliosis is unknown. Glial expression of some MMPs
is regulated by cytokines, and concomitant expression of gelatinase B
and interleukin-6 levels are elevated in the CSF with Lyme
neuroborreliosis.
Moreover, co-incubation of C6 glioma cells with B. Burgdorferi
induces the expression of IL-6. It is possibke that MMP and IL-6
expression are regulated by similar, as yet unknown, mechanism, We
found that primary cultures of rat neural cells infected with B.
Burgdorferi secrete increased amounts of MMPs compared with
uninfected cultures. It remains to be seen which cell types mediate
this response.
B.burgdorferi is not directly toxic to neurons and it is not known to
express MMP activity; however, B. burgdorferi does bind to glial
cells in vitro. Since MMPs can digest myelin hasic protein, B. burgdorferi could promote CNS injury indirectly by inducing the
expression of MMPs in neural cells.
MMPs also digest at least two proteins of adult CNS extracellular matrix (ECM): the aggregating proteoglycan versican and tenascin. The extracellular matrix (ECM) helps maintain the structural integrity of the CNS and facilitates cell migration, ion transport, and growth factor delivery. Thus, digestion of the brain extracellular matrix could promote the migration and disemination of B.- burgdorferi within CNS and could contribute to the neuropathology of Lyme neuroborreliosis.
Muistiin 27.10.2017
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