W8L10 - The Immune System Flashcards
CNS Myelin vs PNS Myelin
PNS myelin is formed from Schwann cells and CNS myelin is formed from oligodendrocytes
Oligodendrocytes can coil around 60 fibres simultaneously and the sheaths they form lack a neurilemma (outer cytoplasmic layer of cells)
The neurilemma remains mostly intact when neurons are damaged and plays a large role in fiber regeneration which is essentially absent in the CNS
Multiple Sclerosis
Chronic disease of the CNS
Sclerotic lesions or plaques in white matter of CNS
- destruction of the myelin sheath surrounding axons
- inflammatory infiltrates of lymphocytes and macrophages (blood vessels)
Variety of neurological symptoms
- muscle weakness
- ataxia
- paralysis
- blindness
Clinical Course of MS
Early
- acute attacks (relapses) followed by reduced illness (remission)
- events leading to remission unknown
Later
- often after decades disease becomes progressive
- steady neurological decline
- chronic neurodegeneration
Risk Factors of MS
Genetic
- 10x more frequent in females
- concordance rate of approx 25% with monozygotic twins (non identical twins 6%)
HLA DRB1*1501 has strongest association (this allele not associated with any other immune disease)
Environmental
- Epstein-Barr virus and smoking - sustained activation of immune system
- low vitamin D - effect differentiation of T cells
Immunopathology of MS
T cell mediated neurological disease results in destruction of the myelin sheath
Antigens:
- myelin basic protein (MBP), proteolipid protein (PLP), myelin oligodendrocyte glycoprotein (MOG)
- autoreactive T helper cells cross blood brain barrier
CD4 T cells (TH1 and TH17) react against myelin antigens
- release of IFN-ɣ, IL-17
- activated TH1 cells secreting IFN-ɣ, activating macrophages, which secrete proteases and cytokines
- IL-17 stimulates macrophages, inflammation (however no neutrophil infiltrate seen in MS)
MS Mouse Model
Mice injected with myelin developed a similar neurological disease
- experimental autoimmune encephalomyelitis (EAE)
The antigen that induced EAE were:
- myelin basic protein (MBP)
- proteolipid protein (PLP)
- myelin oligodendrocyte glycoprotein (MOG)
Antigen specific T cells from EAE affected mice were injected to health mice which then developed EAE
- adoptive transfer: transfer of T cells specific for these myelin antigen induced the disease
T cells specific for these antigen have been found in blood and CSF of patients with MS
Activation of MS
Primary activation by intrinsic antigens:
- damaging event in the CNS (damage to oligodendrocytes that make the myelin sheath)
- leak of antigens through endothelium of CNS
- antigen taken up and presented to CD4 T cells - then pass through leaky endothelium
- release cytokines to initiate inflammatory damage
Primary activation by extrinsic antigens:
- event in peripheral tissue (skin, intestines, lungs) such as infection
- antigen taken up and presented to CD4 T cells
- CD4 T cells expressing α4:β1 integrin (VLA-4) bind VCAM on endothelial cells and cross blood brain barrier and encounter autoantigen presented by resident microglial cells
- molecular mimicry
- release cytokines to initiate inflammatory damage
Treatment of MS
Immunosuppressive drugs
- corticosteroids
Subcutaneous injections of IFN-β (anti-inflammatory)
- thought to alter cytokine response
Natalizumab - antibody against α4 integrin (very late antigen 4, VLA-4)
- blocks migration of T lymphocytes to the CNS
- very successful in many patient!
- some patients had reactivation of JC virus causing progressive multifocal leukoencephalopathy (PML)!
Fingolimod (FTY720)
- blocks shingosine 1-phosphate mediated pathway of T cells
- also inhibits migration
Administration of MBP
- induce tolerance to this antigen
Treatments effective in early stage but less in progressive stage
Peripheral Nephropathies
Diverse group of diseases
Antibodies directed against ganglioside antigens
- glycosphingolipid linked to sialic acid and sugar chain (on the surface of nerve cells)
- antibodies found in many people with peripheral autoimmune nerve disorders
Examples of diseases:
- chronic sensorimotor demyelinating neuropathy
- chronic ataxia neuropathy
Guillain Barre Syndrome (Acute Idiopathic Polyneuritis)
Immune destruction of myelin sheath around axons of peripheral nerves
- fast onset (1 day) with pain, tingling and weakness
- can be fatal (15%) if breathing muscles effected
- most cases (70%) follow from infection (Campylobacter, CMV, influenza)
Different forms:
1. Acute motor axonal neuropathy (AMAN)
- prominent motor involvement
- antibodies to GM1, GD1a, GM1b, GaINAc-GD1a
2. Acute inflammatory demyelinating polyneuropathy (AIDP)
- antibodies to GQ1b and GT1a in 90% of cases
Infection with GBS
Most cases (70%) follow an infection (molecular mimicry) Almost all are GI tract or respiratory tract infections - Campylobacter jejuni has been associated with 30% of cases - CMV associated with 10% of cases
Immunopathology of the Two Types of GBS (AMAN and AIDP)
Acute motor axonal neuropathy (AMAN)
- axonal form is mediated IgG antibodies directed against the cell membrane covering the axon (nodes of Ranvier) => complement activation
Acute inflammatory demyelinating polyneuropathy (AIDP)
- demyelinating form of GBS features damage to the myelin sheath by T cells and macrophages (antibodies involved => complement => opsonisation)
Treatment of GBS
GBS is considered an emergency - sudden onset
Treatment:
1. Plasmapheresis
- removing plasma thus removing autoantibodies
2. Intravenous immunoglobulin therapy
- antibodies from donors block autoantibodies
Immunosuppressive therapies have not worked
Most recover in a few weeks, however some have symptoms for up to 3 years
Rarely fatal
Schizophrenia
Inability to distinguish reality from non-reality
Types:
1. Catatonic - little or no movement
2. Disorganised - inappropriate emotions, disorganised thinking
3. Paranoid - delusions, hallucinations, false beliefs of grandeur
4. Residual - long term, most symptoms disappeared, but flat effective
5. Undifferentiated - not in above categories, mix of types
Schizophrenia Immunology
Antibodies against brain tissue and other structures
- no correlation with Abs to brain?
However, it has been reported that these patients have a predisposition to elevated B cell response
- genetic variations that also results in increased B cell response?
- antibody response results in or is as a consequence to schizophrenia?
- genetic variation / B cell response results in autoimmune pathology following infectious episode
T cell response
- heterogeneity of disease, medications
