NEUROIMMUNOLOGY

MBChB/BDS III
25 February 2022
Virtual Lecture
08:00 Hrs-0900 Hrs
Professor L.S. Zijenah
 Introduction
• The central & peripheral nervous systems are not
excluded from immune diseases.
• The immune system participates in nervous tissue
to counteract infection & immune cells enter these
tissues in inflammation.
• T & B lymphocytes as well as neutrophils,
monocytes & MΦs can invade inflamed nervous
tissue.
• B lymphocytes are responsible for synthesis of
Abs found in the cerebrospinal fluid (CSF).
• T cells & MΦs whilst protecting against infection
may cause direct damage.
(1) Infections Of The Central Nervous System
{CNS} & Peripheral Nervous System {PNS}]:
• The Blood-Brain Barrier (3B) normally excludes
intravascular proteins (including IgG) & this
must be breached before extrathecal circulating
autoAbs reach the CNS & PNS.
• Infections of the CNS, meningitis & encephalitis
are rare in immuno-competent individuals.
• Severe, unusual or recurrent brain infections
should raise the possibility of an immune defect;
e.g. in HIV infection.
 (i) HIV/AIDS
• In HIV positive patients (pts), opportunistic microorganisms:
viruses, fungi, parasites or bacteria may infect the CNS.
• HIV itself may infect the brain producing a range of
problems including AIDS dementia.
• Neurological abnormalities occur in 50% of HIV infected
adults & in many HIV infected chn.
• Up to 75% of brains of AIDS patients are found to be
affected post-mortem.
• Pathological changes range from white matter pallor & mild
lymphocytic infiltration to MΦ abnormalities (including
multinucleate giant cells) associated with MΦ activation .
 Neurological complications of HIV
infection:
• (a) Primary HIV infection:
Dementia, atypical meningitis & myelopathy.
• (b) Opportunistic infections:
Cerebral toxoplasmosis, Meningitis
(cryptococcal or tuberculous), CMV/HSV
encephalitis, CMV retinitis & Progressive
multifocal leucoencephalopathy (papovavirus).
• (c) Tumours:
Kaposi’s sarcoma & B cell lymphoma.
(ii) Parainfectious Encephalitis (PE):
• Infections can result in damage even after the
pathogen has been eliminated.
• PE is a demyelinating disease which occurs
some time following a childhood viral illness
(rubella, or measles or chicken pox).
• The demyelination is due to bystander activation
of T cells or molecular mimicry resulting in T
cells mistaking myelin for virus.
•  PE is self-limiting, however permanent damage
or death may result.
 (iii) Subacute Sclerosing Pan-
encephalitis (SSPE)
• In contrast to PE, SSPE is a rare, progressive
disease of chn, who present with insidious
dementia.
• Follows measles infection several years earlier.
• Anti-measles Abs as well as the virus are found in
brain, blood & CSF.
• No evidence of defective adaptive immune
response to measles virus- these chn may have
defective innate immunity e.g. abnormal Toll-like
receptors important in early protection against
many viruses.
(iv) Progressive multifocal leucoencephalopathy
• Rare demyelinating disease, induced by
papovaviruses.
• Typically occurs in immunosuppressed patients
e.g. AIDS or those receiving immunosuppressive
Rx including therapeutic Mabs, particularly
Natalizumab (mab to α4β1integrin), which
blocks integrins required for migration of
leucocytes that would control the papovavirus.
• ? Pathogenesis.
(2) Demyelinating diseases of the CNS
(i) Multiple Sclerosis (MS)
• MS is common in Caucasians (1 case per 2,000
population).
• It is an inflammatory disease of white matter
(WM) in the CNS.
• It is a highly variable disease, in terms of
disability, rate of disease progression &
prognosis.
• Pathological lesion in MS, seen at postmortem
brain biopsy, is a plaque in WM area.
• Myelin sheath & oligodendrocytes (ODs) are
absent in this area.
 (i) Multiple Sclerosis (MS) [II]
• Myelin is a protein-phospholipid material that
surrounds axons in a multilayered dense spiral.
• Myelin sheaths in the CNS are formed by
compacted membranes of OD extensions.
• The integrity of the myelin sheaths depends on
the maintenance of normal oligodendrocyte
function.
• Axons without myelin sheaths are poor
conductors of nerve impulses, resulting in the
neurological deficit.
• In the early stages of plaque, there is oedema,
apoptotic ODs & infiltrating cells; lymphocytes &
MØs are seen around the venules in the area Ig
production & inflammation.
 Diagnosis of MS
• Can be difficult, clinical features depend on site of
pathological lesion in brain, many plaques are
clinically silent.
• A definite histological confirmation by biopsy is
not possible in life.
• Magnetic resonance imaging (MRI) – lesion in
90% cases, however not specific.
• Evoked nerve potential testing – prolonged
responses due to poor nerve conduction.
• Routine CSF investigations unreliable, IgG may
have been synthesized in CNS or passively
transferred from serum.
 Diagnosis of MS (II)
• The concentration of CSF IgG is best expressed in relation to
another serum protein that is not synthesized in the brain,
as this level will indicate the integrity of the blood–CSF
barrier.
• IgG:albumin ratio more reliable (albumin not synthesized in
brain).
• Intracerebral IgG synthesis increase in ratio.
• If raised CSF IgG due to “ leaking” 3Bconstant
IgG:albumin ratio.
• CSF isoelectric focusing has improved diagnostic accuracy.
 Diagnosis of MS (II)

• The oligoclonal pattern of IgG is seen in >95% of

pts with MS.
• Problem: also found in neurosyphilis, optic
neuritis & SSPE, however such conditions rarely
cause diagnostic difficulty.
Oligoclonal pattern of IgG
 Cause of MS & Immunopathogenesis:
• Cause ?
• Environmental & genetic factors are implicated.
• Common in Caucasians with HLA-DR2, DR1 & DQ1
Ags.
Immunopathogenesis ?
• Whether immune cells injure the ODs directly or
whether the damage results from viral or other toxic
agents remains controversial.
• Apoptosis of ODs may precede inflammation &
demyelination.
• CD8+ T lymphocytes may be responsible for the death of
ODs whereas CD4+T lymphocytes may be responsible
for inflammation. MØ may also be involved.
 Treatment:
• No specific treatment that will reverse
demyelination.
• Corticosteroids in acute attacks suppress the
inflammatory responses but this does not stop
disease progression.
• Efficacy of IFN-β & IVIg is controversial.
• Targeted immunotherapy with humanized Abs
has proved successful, e.g. natalizumab (mab to
α4β1integrin), prevents entry of damaging cells
into the WM, serious side effects inhibit its use.
Anti-CD25+Ab (daclizumab), inhibits IL-2
signaling, USA FDA Approved, but
disapproved later due to severe side effects.
 Prognosis:

• Prognosis depends on the disease subtype.

• Overall, 20% have died 20 yrs after diagnosis &

>60% are significantly disabled.
 (ii) Optic Neuritis:

• Inflammatory, demyelinating disease, of

one or both optic nerves.
• Pts: 70-90% recover; 50% develop MS
within 15 yrs.
• Oligoclonal pattern of IgG in most pts.
 (3) Autoimmune diseases of the
Neuromuscular Junction
(i) Myasthenia Gravis (MG)
• An uncommon disease (prevalence 9 per 105
population).
• Characterized by weakness & fatigue of
voluntary muscles including those of the eye.
• Weakness results from impaired neuro-
transmission (Nt) from nerve to muscle at
neuromuscular junctions.
• Nt is impaired by autoAbs to the acetylcholine
receptor in post synaptic membrane of muscle.
• Abs reduce #s of acetylcholine receptors, by complement
mediated lysis & accelerated internalization.
 Aetiology of MG:
• At least four subgroups of pts are recognized (Table
1), suggesting different aetiologies.
• Infectious agents.
• MG in young women (early-onset MG) is an organ
specific autoimmune disease associated with HLA-A1
B8 DR3.
• There are hyperplastic thymic changes in early-onset
MG, in contrast to those with a thymic tumour.
Table 1: Heterogeneity of myasthenia gravis

Young women Older men (late- Thymoma No AcChR Ab

(early-onset MG) onset MG

Proportion of pts 40–50% 15-30% 15-20% 15%

Thymic changes Hyperplasia Atrophy Tumour Unknown

Ab titre to AcChR High Low Intermediate None/MuSK/

Other Abs
Muscle weakness Systemic Systemic/Ocular Systemic Systemic/Ocular

Immunological Thymectomy Prednisolone + Thymectomy for Prednisolone +

therapy (recover in 2 azathioprine tumour, if little azathioprine
years) plus improvement in
immune weakness -
suppression important to use
immune
suppression as
well

HLA associations A1 B8 DR3 B7 DR2 None None

 DIAGNOSIS:
• Presence of acetylcholine receptor Ab (Positive
in 90% of younger pts & 60% pts with
myasthenia confined to the ocular muscles).
• Only 10% of babies of myasthenic mothers
develop neonatal myasthenia, since the receptor
Abs are neutralized by fetal production of
antiidiotypic Abs, presumably IgM.
• ~10% of myasthenic pts who are seronegative for
anti-AChR Abs will instead have autoAbs to
muscle-specific receptor tyrosine kinase (MuSK)
& other autoAbs which may also be pathogenic.
 Treatment of MG
• Symptomatic management of MG is achieved
using acetylcholinesterase inhibitors
(Neostigmine, Physostigmine &
Pyridostigmine).
• Longer term Rx involves suppression of
production of acetylcholine receptor Abs (e.g.
with prednisolone and azathioprine).
• Thymectomy in those with an enlarged thymus
or thymoma removes not only some of the
plasma cells producing the Abs but also at least
one source of Ag.
 Rx of MG
• Pts with severe MG respond well to
plasmapheresis or high-dose IV Ig in
extreme cases), in addition to
immunosuppressive therapy.
Other autoimmune diseases of muscle
end-plates
• (i) Lambert-Eaton Myasthenic Syndrome
• AutoAbs to Ca2+ channels related to the release of
acetylcholine from vesicles result in muscle weakness. Rx
similar to MG
• (ii) Stiff person syndrome (SPS) caused by autoAbs to
glutamic acid decarboxylase (GAD, which results in
inability to relax muscles by breaking down the transmitter.
• SPS is always associated with type 1 diabetes in which the
GAD autoAbs are also pathogenic.
(4) Immune-mediated neuropathies
• Peripheral neuropathy can be a
complication of common immune
mediated diseases e.g. RA or diabetes
mellitus or a common feature of rare
diseases e.g. polyarteritis nodosa or
amyloidosis.
(i) Acute idiopathic polyneuritis (Guillain-Barre
syndrome); {GBS})

• Uncommon disease of subacute onset in which

there is infiltration of the PNS with lymphocytes
& MØs,  myelin destruction.
• 50% of GBS occurs in relationship to an
infectious illness, often a diarrhoeal illness due
to Campylobacter jejuni.
• 10% follow surgical procedure & the rest are
idiopathic.
 Pathogenesis of GBS
• Involves production of autoAbs to peripheral
nerve gangliosides triggered by infection.
• There is an increase in CSF proteins including
IgG which often is oligoclonal.
• Abs to GM1b, GD1a, GT1a and GQ1b,
gangliosides detected in 70% of pts.
• Molecular mimicry between gangliosides &
infectious agents precede these conditions.
• Early complement activation, based on Ab
binding to the outer surface of the Schwann cell,
results in deposition of activated complement
components & this seems to initiate the damage
to myelin.
 GBS pathogenesis/Rx
• Infiltration by MΦs occurs a few days after
complement-mediated myelin damage.
• Pts undergo a lumbar puncture to rule out
infectious diseases, such as Lyme disease, or
malignant conditions, such as lymphoma.
• Most pts recover within few wks of onset, their
recovery is usually complete & therapy is
avoided.
• In severely affected pts, IV Ig is given.
• Plasma exchange has proven efficacy in GBS pts.
(ii) Chronic inflammatory peripheral neuropathies
• Unlike GBS, may be relapsing & remitting or
have a progressive course.
• The main chronic autoimmune neuropathies
include chronic inflammatory demyelinating
polyneuropathy (CIDP), multifocal motor
neuropathy (MMN) & anti-myelin- associated
glycoprotein (MAG) demyelinating neuropathy.
 Chronic inflammatory demyelinating
polyneuropathy (CIDP)
• Pts are usually middle-aged & symptoms
present gradually.
• The prevalence is ~ 30 per 105 population.
• The aetiology remains obscure.
• Demyelination is multifocal, affecting spinal
roots, plexuses & proximal nerve trunks, so that
the clinical picture is variable.
 Pathogenesis
• Pathogenesis is thought to be mixed, cellular &
humoral.
• A significant proportion of infiltrating γδ T cells
are able to recognize glycolipid & carbohydrate
moieties suggesting involvement of NK cells,
which are thought to activate residing MΦs,
leading to phagocytosis & production of
proinflammatory cytokines.
 Multifocal motor neuropathy (MMN)
• MMN is a distinct disease that should be
recognized early because it is treatable.
• It presents with progressive weakness, atrophy
& loss of reflexes that usually begin in the hands
& is prominent in distal muscle groups.
• It differs from vasculitic neuropathy because it is
slow & painless & affects only motor nerve
fibres.
• Pts have purely motor symptoms, which are
usually symmetrical.
 Pathogenesis/Rx
• The pathogenesis of MMN is poorly understood.
• AutoAbs against gangliosides (GM1, GD1a and
GD1b) are present in up to 60% of pts.
• The condition is exacerbated by steroid therapy.
• High-dose IV Ig is now the Rx of choice, since.
• Maintenance therapy with Ig then enables the
pts to live disability-free lives.
 Monoclonal gammopathies (MG)
• Sensory or motor neuropathies have been
described in pts with MG.
• 50% of pts with MG have Mabs to myelin-
associated glycoprotein – a major component of
peripheral nerve.  
• These Abs have been shown to cause
demyelination in animals.
• Pts often present with sensory ataxia & have a
distinctive pattern on nerve conduction studies.
Treatment:
• Plasmapheresis with or without immuno-
suppressives.
 Paraneoplastic syndromes (PS)
• Inappropriate expression of tumour-associated
Ags that cross-react with those on normal tissues
can be caused by a number of mechanisms in
tumours, including mutations, rearrangements
of the genome & viral insertions.
• PS can affect any organ or system.
• Most classic PS are associated with Abs to
intracellular (onconeuronal) Ags, appear to be
mediated by CTL responses & have limited
response to Rx.
• These pts nearly always have a malignancy,
often covertly.
 Paraneoplastic syndromes (PS)
• E.g. LEMS pts may or may not have an
associated cancer, such as small cell lung cancer
(Table 2).
• The neurological syndrome may predate an
overt malignancy by many years, so it is always
important to search for a resectable cancer,
especially in the lung.
Table 2: Paraneoplastic syndromes

Condition Signs Cancer AutoAbs to:

LEMS Fatigue ability of muscles Small cell Voltage gated
causing weakness lung (SCL) Calcium channels
cancer

Neuromyelitis Relapsing optic neuritis, Thymoma or Aquaporin 4

optica transverse myelitis, other tumours
encephalopathies
Cerebellar Ataxia, brainstem Small cell Voltage gated
degeneration encephalitis lung cancer Calcium channels

Limbic Dementia SCL cancer, Voltage gated

encephalitis thymoma, Calcium channels
adenocarcino
ma of breast,
prostate
Table 2: Paraneoplastic syndromes

Conditions Signs Cancer AutoAb to:

Paraneoplastic Sensory loss & a Small Cell Lung Neuron antigen –

sensory reflexia cancer Hu
neuropathy

Sensorimotor Mononeuritis Cancer or

neuropathy multiplex vasculitis

Paraproteinaemic Motor & sensory Lymphoid Myelin Associated

polyneuropathies loss malignancies Glycoprotein
 Cerebral SLE
• 60% of pts with SLE suffer neuropsychiatric
episodes at some time:
• Most pts experience only mild but fluctuating
symptoms.
• Spontaneous improvement in some pts;
irreversible changes in others.
• Cerebral thrombosis is not infrequent & is
associated with clotting factors & phospholipids.

 
 Thank you for your attention.
• Stay blessed.