)
Table of contents :
(before and after transplantations)
(cancer chemotherapy and some immunosuppressive
drugs)
deficiency => urticaria-necrotizing
vasculitis / angioitis;
e.g. Streptococcus
pneumoniae,
Haemophilus
influenzae)
deficiency => acquired angioedema,
lung
carcinomas),
invasive
fungal infections,
intracellular bacteria (Salmonella
spp.,
Mycobacterium
spp.,
viruses
(reactivation of herpesviruses, expecially HHV-1
/ HSV-1,
HHV-3
/ VZV,
HHV-5
/ CMV)
: in the case of perinatal HIV-1
infection even AMI is compromised due to deficiency of memory
B cells.
;
e.g. Streptococcus
pneumoniae,
Haemophilus
influenzae)
as after splenectomy, gram positive bacteria (Staphylococcus
aureus),
rotavirus
and parvovirus
(due to decreased IgA on mucosal surfaces)
and Serratia spp.
or transfusions
(dwarfism, ..),
splenomegaly
that look for type
IV hypersensitivities
after vaccinations or infection
and affect ~ 3-5% of the population with 2/3 of the patients being women.
The site of attack is organ- or tissue-specific or more systemic : as the
self-antigen(s) is usually expressed in more than one cell type, from an
anatomical point of view autoimmune diseases should more properly be enclosed
among the multi-organ failures (MOF).
Anyway, due to common pathogenesis, I prefer to group them globally among
the diseases affecting the immune system : a link to this page is provided
in every page regarding involved organs. They can be classified as follows
according to the main targeted organ(s) / apparatus(es) :
=> macrophages obstruct trabeculate, but no lymphocyte infiltration occurs
or panuveitis,
vertigo, nausea and vomiting,
very deep pain in the eyes => uveitis
(first one eye and in a couple of weeks the other eye may become affected)
with preservation of the choriocapillaris (thanks to anti-inflammatory
products secreted by the retinal pigment epithelium, including TGF-b
and cystatin
C / retinal pigment epithelial protective protein that is known to
suppress the phagocyte generation of superoxide) and retina (despite extensive
inflammatory cell infiltration in the choroid) => retinal
detachment
=> rapid vision loss, drowsiness, alopecia areata,
autoimmune
vitiligo, poliosis, hearing loss, facial
nerve palsies,
rigidity, walking (gait) disturbance
and cataract.
or interphotoreceptor
retinoid-binding protein (IRBP).
,
and even prostration, tinnitus (varying from a whistle to a roar),
and deafness. The onset of symptoms is insidious, usually with a
sensation of dullness or fullness in the ear, and an initial fluctuation
in hearing of 10 to 30 dB, usually in the low tones. The hearing improves
somewhat between attacks, but it continues to deteriorate as time goes
on. There may be increased sensitivity to sound, or music may sound distorted.
Any head movement aggravates the condition, with the vertigo lasting several
hours. Some patients can have fleeting attacks lasting several minutes,
and still others have attacks lasting a week or longer and may take months
to regain normal equilibrium.
,
regimen of bed rest, no smoking, plus inhalation of 5% CO2 +
95% O2 for 30' q.i.d. and 2.75 mg of histamine
diphosphate
in 250 cc of lactated Ringer's solution I.V. b.i.d. Other drugs, given
individually, that are reported to be effective for an acute attack are
1/150 grain atropine
I.V., diazepam
10 mgm I.V., and fentanyl citrate
+ droperidol,
which must be administered in the hospital or by an anesthesiologist. Vasodilators
are usually ineffective in Meniere's, as are the antivertiginous
drugs.
infectionmajor
core protein lambda 1,
tinnitus, nausea and vomiting,
and sudden hearing loss (SHL) which develop within several months of each
other => bilateral deafness (67%),
and RPR
and/or CT
should be done primarily to rule out cerebellopontine angle (CPA) tumors.
MRI may show enhancement of vestibular and cochlear structures with gadolinium.
: topical for IK and oral for vestibuloauditory involvement (prednisone
1 mg/kg for 2-4 weeks)
(?)
gene is mapped approximately at 200 kb telomeric to HLA-A on chromosome
6. It has 11 SNPs : allele C is in linkage disequilibrium with HLA-A11
(P<0.00001) and to a lesser extent with HLA-A1 (P<0.01).
,
molecular mimicry is presumed as trigger for this disease.
/ Charcot's diseaseref
: positive RT-PCR on neuronal cell bodies within the gray matter of the
spinal cord in 88.3% of patients vs. 3.4% of controlsrefref
(OR: 3.2; p = 0.102)ref
(OR: 8.4; p = 0.064)ref,
and BDNF,
increased ROS and Glu. Immature (DEC205, CD1a) and activated/mature (CD83,
CD40) DC transcripts are significantly elevated in ALS ventral horn and
corticospinal tracts. Monocytic/macrophage/microglial transcripts (CD14,
CD18, SR-A, CD68) are increased in ALS spinal cord, and activated CD68+
cells were demonstrated in close proximity to motor neurons. mRNA expressions
of MCP-1 by glial cells, which attracts monocytes and mDCs, and of CSF-1
/ M-CSF
are increased in ALS tissues. Those patients who progressed most rapidly
expressed significantly more dendritic transcripts than patients who progressed
more slowlyref.
High titer of IgM anti-GM1 antibodies are detected in serum
of 46% LMND patients, 80% of MN patients, and 18% of the classical ALS
casesref.
=> chronic encephalitis confined to one hemisphere and contralateral cerebellar
hemi-atrophy. In the active phase, neuronophagia, activated microglial
cells (rod cells), microglial nodules, and perivascular lymphocytic infiltrates,
are present. In the more chronic phase neuronal loss and gliosis predominate.
enteritis
),
stiff neck, and confusion; these are followed by focal seizures, paralysis,
progressively deepening coma, and death.
(1 every 1,000 cases)
(1 every 4,000-10,000 cases)
(1-2 every 1,000,000 immunizations)ref,
meningismus, headache,
nausea
and vomiting,
and drowsiness progressing to lethargy and coma; disseminated neurological
disease => pyramidal signs, tremor, cerebellar involvement (expecially
in ADEM due to HHV-3
/ VZV),
seizures, paralysis, ...
(protidorrachy = 50-150 mg/dL), lymphocytary pleiocytosis (< 200 cell/mL;
sometimes higher or with PMN in the first days of disease), oligoclonal
bands
: diffuse symmetric contrast enhancement in white matter of encephalon
and spinal cord,
ACTH,
and plasmapheresis
(more cycles if relapses occur)
or more are 40% less likely to develop MSref.
The link with sunshine may explain why MS is more common in high latitudes
seropositivity is strongly associated with risk of progressive MS (OR =
7.3)
(OR = 2.1) : the risk of MS increased monotonically with serum titers of
IgG antibodies to VCA or EBNA complexref
after 15 years of age (OR = 2.3)
after 15 years of age (OR = 2.8)
does not increase the risk of developing multiple sclerosis or cause exacerbationsref1,
ref2,
ref3,
ref4,
ref5,
ref6,
ref7,
ref8
polarization (but also Th2)
=> perivenular cuffing by inflammatory cells (BBB is disrupted but,
unlike vasculitis, the vessel wall is preserved) and necrosis of oligodendrocytes
(sometimes vascular demyelinization) => gray-to-pink plaques of
demyelination of various sizes (1-2 mm to many cm) throughout the white
matter of the CNS, sometimes extending into the gray matter, most commonly
in periventricular areas (lateral angles of lateral ventricles) with a
net border between normal and affected areas => cicatricial gliosis.
Survived oligodendrocytes try to remyelinate some fibers (shadow plaques)
but they are finally desroyed. Hyaluronan accumulates in demyelinated lesions
and inhibits oligodendrocyte progenitor maturationref.
At least 4 fundamentally different neuropathological patterns can be discerned.
Patterns I and II lesion pathologies are modeled in the current virus-
and autoimmune-based animal models of encephalomyelitis that have been
established in susceptible rodent strains or non-human primates. MS is
characterized by periodic relapses correlated with microbial infections,
most commonly URT infections (Influenzaviruses).
Several possible mechanisms may explain this link :
that are quantitatively related to a reduction in functional suppression
induced during suboptimal T-cell receptor (TCR) ligation. Of importance,
this observation links a defect in functional peripheral immunoregulation
to an established genetic marker that has been unequivocally shown to be
involved in maintaining immune tolerance and preventing autoimmune diseases.
Diminished FOXP3 levels thus indicate impaired immunoregulation by Tregs
that may contribute to MS. Future studies will evaluate the effects of
therapies known to influence Treg cell function and FOXP3 expression, including
TCR peptide vaccination and supplemental estrogenref.
CD4+CD25hi TReg cells (not diluted by
recently activated cells involved in the ongoing MS-associated immune response)
isolated from MS patients markedly fail to suppress CD4+CD25-
T-cell proliferation and IFN-g production induced
by plate-bound CD3-specific antibodyref.
-W
encoded viral envelope glycoprotein syncytin
is upregulated in glial cells within acute demyelinating lesions of multiple
sclerosis patients. Syncytin expression in astrocytes induced the release
of redox reactants, which were cytotoxic to oligodendrocytes. Syncytin-mediated
neuroinflammation and death of oligodendrocytes, with the ensuing neurobehavioral
deficits, were prevented by the antioxidant ferulic acid in a mouse model
of multiple sclerosis. Thus, syncytin's proinflammatory properties in the
nervous system demonstrate a novel role for an endogenous retrovirus protein,
which may be a target for therapeutic interventionref.
Leptin
production was significantly increased in both serum and CSF of naïve-to-therapy
relapsing-remitting multiple sclerosis (RRMS) patients and correlated with
IFN-g secretion in the CSF. T cell lines against
human myelin basic protein (hMBP) produced immunoreactive leptin and up-regulated
the expression of the leptin receptor (ObR) after activation with hMBP.
Treatment with either anti-leptin or anti-leptin-receptor neutralizing
antibodies inhibited in vitro proliferation in response to hMBP. Interestingly,
in the RRMS patients, an inverse correlation between serum leptin and percentage
of circulating TRegs was also observed. To better analyze the
finding, we enumerated TRegs in leptin-deficient (ob/ob)
and leptin-receptor-deficient (db/db) mice and observed the
significant increase in TRegs. Moreover, treatment of WT mice
with soluble ObR fusion protein (ObR:Fc) increased the percentage of TRegs
and ameliorated the clinical course and progression of disease in proteolipid
protein peptide (PLP139-151)-induced relapsing-experimental
autoimmune encephalomyelitis (R-EAE), an animal model of RRMS. These findings
show an inverse relationship between leptin secretion and the frequency
of TRegs in RRMS and may have implications for the pathogenesis
of and therapy for multiple sclerosisref.
(35%) : weakness of the limbs may manifest as loss of strength or dexterity,
fatigue, or a disturbance of gait. Exercise-induced weakness is a characteristic
symptom of MS. The weakness is of the upper motor neuron type and is frequently
accompanied by other pyramidal signs such as spasticity, hyperreflexia
and Babinski signs. Occasionally, a tendon reflex may be lost (simulating
a lower motor neuron lesion) if an MS lesion disrupts the afferent reflex
fibers in the spinal cord..
However, unlike Bell's palsy, facial weakness in MS is generally not associated
with ipsilateral loss of taste sensation or retroauricular pain
(37%)
(24-32%)
(36%) => decreased visus (2-22.3%; higher in youngs); it regress completely
thanks to resorption of the edema, which initially is mild. At following
attacks regression is only partial as gliosis is irreversible. It generally
presents as diminished visual acuity, dimness, or decreased color perception
(desaturation) in the central field of vision. These symptoms may be mild
or may progress to severe visual loss. Rarely, there is complete loss of
light perception. Periorbital pain (aggravated by eye movement) often precedes
or accompanies the visual loss. An afferent pupillary defect may be found.
Funduscopic examination may be normal or reveal optic disc swelling (papillitis).
Pallor of the optic disc (optic atrophy) commonly follows ON. Uveitis
is rare and should raise the possibility of alternative diagnoses. Visual
blurring in MS may result from ON or diplopia. Visual blurring that resolves
when either eye is covered is due to diplopia.
or hyposthenia of extraocular muscles due to involvement of brainstem nuclei
(expecially rectus lateralis > those innervated by III or IV cranial nerves)
=> diplopia
(11-15%) and acquired pendular nystagmus of abduced eye with a mild
oblique deviation (skew deviation)
(0.3%)
(1%), hemifacial spasm, and glossopharyngeal neuralgia can occur when the
demyelinating lesion involves the root entry (or exit) zone of the fifth,
seventh, and ninth cranial nerve, respectively. Trigeminal neuralgia (tic
douloureux) is a very brief lancinating facial pain often triggered by
an afferent input from the face or teeth. Most cases of trigeminal neuralgia
are not MS-related. However, the occurrence of atypical features such as
the onset before age 50 years, bilateral symptoms, objective sensory loss,
or nonparoxysmal pain should raise concerns that a symptomatic cause such
as MS is responsible.
(1-1.3%) due to involvement of brainstem nuclei---CD178
/ FasL
interaction-dependent manner. More common in elderlies
(5%)
(0.59%)
(3.6-6%) may appear suddenly and resemble acute labyrinthitis. A brainstem
rather than end-organ origin is suggested by the presence of coexisting
trigeminal or facial nerve involvement; vertical nystagmus; or nystagmus
that has no latency to onset, no direction reversal, and doesn't fatigue.
Hearing loss may also occur in MS but is uncommon.
(11%)
(3%)
(1.6%)
(2.6%)
(1.6%)
(1%) : men report impotence, less desire, impaired genital sensation, impaired
ejaculation, and inability to achieve/maintain an erection. Women report
genital numbness, diminished orgasmic response, decreased libido, unpleasant
sensations during intercourse, and diminished vaginal lubrication. Adductor
spasticity (in women) can also interfere with intercourse, and urinary
incontinence (in either men or women) can be problematic.
(> 90%) : urge incontinence in weekly or more frequent episodes (33%),
urinary retention, or micturition exitation
(1%) consists of either persistent rapid flickering contractions of the
facial musculature (especially the lower portion of the orbicularis oculus)
or a contraction that slowly spreads across the face. It results from lesions
of the corticobulbar tracts or brainstem course of the facial nerve.
(0.3-1%)
(50%). Cognitive dysfunction sufficient to impair activities of daily living
also occurs in 20%
can be reactive, endogenous, or part of the illness itself and can contribute
to fatigue (50-60% along whole course; suicide has RR = 7.5)
(3%) is the electric shock–like sensation (evoked by neck flexion or other
movement) that radiates down the back into the legs. Rarely, it radiates
into the arms. It is generally self-limited but may persist for years.
Lhermitte's symptom can also occur with other disorders of the cervical
spine (e.g., cervical spondylosis).has
demonstrated bursts of disease activity 7 to 10 times more frequently than
is clinically apparent. This finding indicates that there is a large reservoir
of subclinical disease activity in MS, especially during the early stages
of the disease. The triggers causing these bursts are unknown, although
the fact that patients may experience relapses after nonspecific upper
respiratory infections suggests that either molecular mimicry between viruses
and myelin antigens or viral superantigens activating pathogenic T cells
may play a role in MS pathogenesis. Within 15 years from onset,
50% (the great majority of RRMS ultimately) develop ...
(plaques don't captate : differential diagnosis with cerebral vasculitides);
impaired BBB is seen by extravasation of Gd-DPTA (sensitivity > 95%); Gd-enhancement
persists for up to 3 months, and the residual MS plaque remains visible
indefinitely as a focal area of hyperintensity (a lesion) on spin-echo
(T2-weighted) and proton-density images. Lesions are frequently oriented
perpendicular to the ventricular surface, corresponding to the pathologic
pattern of perivenous demyelination (Dawson's fingers). Lesions
are multifocal within the brain, brainstem, and spinal cord. Lesions in
the anterior corpus callosum are helpful diagnostically because this site
is usually spared in cerebrovascular disease. Different criteria for the
use of MRI in the diagnosis of MS have been proposed. The total volume
of T2-weighted signal abnormality (the "burden of disease") shows a significant
(albeit weak) correlation with clinical disability. Approximately one-third
of T2-weighted lesions appear as hypointense lesions (black holes) on T1-weighted
imaging. Black holes may be a better marker of irreversible demyelination
and axonal loss than T2 hyperintensities, although even this measure depends
upon the timing of the image acquisition (e.g., most acute Gd-enhancing
T2 lesions are T1 dark). Newer MRI measures such as brain atrophy, magnetization
transfer ratio (MTR) imaging and proton magnetic resonance spectroscopic
imaging (MRSI) may ultimately serve as surrogate markers of clinical disability.
For example, MRSI can quantitate molecules such as N-acetyl aspartate (NAA),
which is a marker of axonal integrity, and MTR may be able to distinguish
demyelination from edema.
: intratechal IgG synthesis (> 2 oligoclonal bands in 75-90%), mononucleated
pleiocytosis > 5 cell/mL (usually < 20/mL,
> 50/mL in myelopathies; improbable when > 75/mL)
(> 25%), and protidorrachy < 100 mg/dL (differential diagnosis with
infections and tumors if higher)
(at least 1 in 80-90%) provide the most information when the pathways studied
are clinically uninvolved. For example, in a patient with a remitting and
relapsing spinal cord syndrome with sensory deficits in the legs, an abnormal
somatosensory EP following posterior tibial nerve stimulation provides
little new information. By contrast, an abnormal visual EP in this circumstance
would permit a diagnosis of clinically definite MS. Abnormalities on one
or more EP modalities occur in 80 to 90% of MS patients. EP abnormalities
are not specific to MS, although a marked delay in the latency of a specific
EP component (as opposed to a reduced amplitude) is suggestive of demyelination.,
IFN-b1band
IFN-t)
decrease BBB permeability (once the BBB breaks, massive infiltration of
T cells, augmented expression of adhesion molecules on endothelial cell
surface, and leakage of inflammatory cytokines and antibodies will aggravate
the MS lesions))
(mitoxantrone) : 12 mg/m2 in 100 mL (60 gtt/min) every 3 months
up to 120 mg/m2 (8-10 doses)
in SPMS
agonists (methylprednisolone
1 g in 500 mL of slow-drop physiological solution for 5 consecutive mornings)
+ gastric protectants since day before or same day if i.v. => then decreasing
dose (125 mg in p.o. vials q.d. for 7 days => a.d. for 15 days)ref1,
ref2, ref3,
rituximab
?)
prevents expression of CIITA in all cell types that need IFN-g
to express MHC class II molecules, including neurons. Further atorvastatin,
but not pravastatin, stabilizes LFA-1 interactions
for 6 months decreases the number and size of cerebral lesions by around
40% in a 30-patient clinical trial : it is not clear if the drug also eased
the symptoms of MS, which commonly include fatigue, tremor and paralysis,
as the study was not designed to assess this, but prolonged use will help
users live a more normal life.
: paralysed mice became increasingly active just 10 days after receiving
the intravenous injection of 1 million cultured brain stem cells. Over
40% of them turn into cells that make myelinref
and 4-aminopyridine to improve conduction blocks)
stings along the backref1,
ref2,
ref3,
ref4,
ref5,
ref6,
polyosol and bee pollen
provided relief from some of the painful symptoms of MS, but independent
physiotherapists failed to find hard evidence of reduced muscle stiffness
and disability. However, new data presented at the annual meeting of the
British Association for the Advancement of Science in Exeter, UK, indicates
that this assessment might have been premature. Of the patients in the
initial trial, 80% opted to continue cannabinoid treatment for up to 1
year. In the longer term, there is a suggestion of a more useful beneficial
effect, which was not clear at the initial stage. Animal studies have indicated
that cannabinoids slow nerve-cell death-mediated
inflammatory demyelinating disorder of the CNS induced by immunization
of mice and rats with Freund's
complete adjuvant together with ...
heals EAE and worsens MS, while TNF-a
heals MS and worsens EAE. Just before the onset of disease, the animals'
leptin levels double : but in mice that ate nothing for 48 hours - the
equivalent of 7 to 10 days for humans - the leptin surge was smaller. Neurons
in the brain lesions of diseased mice produce leptin.
Mice with a condition akin to MS that were deprived of food for 48 hours
still developed the disease but had fewer brain lesions and performed better
on tests of walking, balance, weakness and paralysis. IL-23
produced by CNS-resident cells controls Th1-cell encephalitogenicity
during the effector phase of EAEref.
SJL mice that express a transgenic TcR specific for PLP (5B6 TcR-transgenic
mice) readily develop spontaneous EAE, unless on the B10.S background,
in which APCs express lower levels of MHC class II and co-stimulatory molecules
(reversed by TLR9 but not TLR4 agonists)ref.
mediated disease
and molecules on caudatus and subthalamic nuclei.
(4-8 weeks after < 10% of infections) and molecules on caudatus and
subthalamic nuclei.
)
or bilateral involuntary movements that gradually become severe, affecting
all motor activities including gait, arm movements, and speech, disappearing
during sleep. A mild psychic component is usually present (obsessive-compulsive
disorder (OCD)).
The disorder may take the form of muscular rigidity (paralytic
chorea).
Westphal's
sign : the patellar reflex evokes a transient maintenance of hyperextension
of leg before falling down (a sign of dystonia).
,
neuroleptics or benzodiazepines
can be used for treatment
(some cases)