Neurological infections and neuro-immunology Flashcards
Why is the response to IVIg poor in autoimmune nodopathy?
IgG4 antibodies in autoimmune nodopathy do not activate complement and have reduced binding to Fc receptors. IVIg blocks complement activation through antibody dilution, making it less effective in a setting when complement activation is not a key aspect of pathogenesis.
What are pros and cons of Rituximab as treatment for anti-MAG neuropathy?
It’s effective in reducing IgM autoantibodies and can lead to improved symptoms and nerve function, even long term.
However, onset of action can take weeks to months, there is a risk of infections due to B cell depletion and efficacy varies highly per patient (
What are the two main pathogenesis routes of autoimmune encephalitis?
Intracellular (T-cell mediated) and cell surface/synaptic antigen (Antibody-mediated)
What is the role of intracellular antigens in autoimmune encephalitis?
Intracellular antigens (such as Yo) are targets of cytotoxic T cells (making neuronal destruction necessary), leading to irreversible neuronal degeneration. This mechanism is typically associated with tumors, particularly teratomas.
Why is T-cell mediated autoimmune encephalitis often associated with tumors?
Tumor-associated antigens can trigger an immune reacton that mistakenly targets normal tissue, leading to exposure of antigens that are usually only found within neurons to cytotoxic T cells.
How do antibodies mediate dysfunction in cell surface antigen-related encephalitis?
Antibodies bind to the extracellular domains of antigens, causing internalization of these antigens (or antigen clusters), or blocking of these antigens, making them unavailable in the synapse and leading to functional disruption of the neuron without neuronal death.
How do T-cell mediated vs antigen-mediated autoimmune encephalitis differ in prognosis?
T-cell mediated has poor recovery rates as it leads to irreversible neuronal degeneration, while cell surface antigen antibody-mediated is ofter reversible with immunotherapy
What is the pathogenesis of anti-NMDAR encephalitis?
Autoantbodies bind to the NR1 subunit of NMDARs, leading to receptor internalization and reduced synaptic density, disrupting glutamate signaling.
What are the consequences of disrupted glutamate signaling?
It weakens excitatory synaptic transmission, leading to cognitive dysfunction and hypoexcitability, pottentially leading to Anxiety, depression and more severe neurological disorders.
What are first-line treatments for T-cell mediated autoimmune encephalitis?
Corticosteroids to reduce T cell activity and plasma exchange to remove inflammatory cytokines and autoantibodies. Effects are limited as this encephalitis is irreversible.
Why is tumor removal important in anti-NMDAR encephalitis?
Ovarian teratomas are strongly associated with anti-NMDAR ecephalitis. Removing the antigen source improves outcomes.
What factors influence treatment response in anti-NMDAR encephalitis?
Early treatment initiation, absence of ICU stay, and
What are first-line treatments for antibody-mediated autoimmune encephalitis?
Corticosteroids (reduce inflammation), IVIg (neutralize autoantibodies, modulate immune response), plasma exchange (remove autoantibodies). High effectiveness.
What are second-line treatments for antibody-mediated autoimmune encephalitis?
Rituximab (anti-CD20) to deplete B cells and reduce autoantibody production. Also cyclophosphamide to suppress B cell activity.
How does the BBB try to keep inflammation in the brain low? (5)
- Less antigen presentation
- Less MHC in neurons
- B cells/antibodies less active
- T cells do not survive or proliferate easily
- Microglia are less primable
What are the 4 possible effects of antibodies in antibody-mediated autoimmune encephalitis?
- Agnostic or antagonistic
- Block of interaction
- Antigenic modulation
- Cytotoxicity
What are the three key pathological features of MS?
Inflammation, demyelination, and axonal loss.
What makes MS a neurodegenerative disease?
In addition to inflammation and demyelination, irreversible axonal degeneration contributes to neurodegeneration.
What is the likely source of early CNS pathology in MS?
It is likely mediated by distinct immune subsets coming from the periphery.
What are the two major risk factor categories for MS?
Genetic (e.g., HLA) and environmental (e.g., Vitamin D, EBV) factors.
What immune cells, in addition to T cells, play a crucial role in MS?
B cells play a crucial role and are new candidates for therapeutic manipulation, especially in progressive MS.
How do T and B cells interact in MS?
T and B cells influence each other’s entry into the brain, with B cells driving the activation of brain-homing autoreactive CD4+ T cells.
Why is studying T- and B-cell subsets important for MS research?
It helps to understand clinical phenomena and contributes to more accurate prediction and treatment strategies for MS.
What is the significance of the BBB in MS pathogenesis?
The BBB serves as one of the main entry points for immune cells, allowing infiltration of pro-inflammatory T cells expressing CCR6.
How do immune cells infiltrate the CNS in MS, and why is CCR6 important?
CCR6+ Th17.1 cells bind to CCL20 on the BBB to migrate into the CNS. VLA-4 aids adhesion, and IL-17 disrupts the barrier, allowing further immune infiltration, leading to inflammation, demyelination, and axonal loss.
Why is genetic evaluation important in Primary Immunodeficiencies (PID)?
Genetic evaluation helps in diagnosis, understanding disease mechanisms, prognosis, and developing targeted therapies.
What are the main genetic testing strategies for PID?
Single-gene Sanger sequencing, gene panel analysis, whole-exome sequencing (WES), and whole-genome sequencing (WGS).
What is the difference between Whole-Exome Sequencing (WES) and Whole-Genome Sequencing (WGS)?
WES focuses on coding regions (~1% of the genome) to find known and novel mutations, while WGS covers the entire genome, including intronic and regulatory mutations.
What is Activated PI3Kδ Syndrome (APDS)?
APDS is a primary immunodeficiency caused by mutations in the PI3Kδ pathway, leading to hyperactive PI3Kδ signalling and resultant T cell senescence and/or death and impaired antibody responses.
What is the function of PI3Kδ?
It is a key kinase complex that is acutely activated in B cells and T cells after exposure to antigen and controls many aspects of lymphocyte development and differentiation
What is the clinical results of APDS?
Frequent infections, autoimmune complications, lung and GI disease, hepatosplenomegaly, and increased risk of lymphoma.
How does Leniolisib target APDS?
Leniolisib selectively inhibits PI3Kδ, restoring immune balance, reducing lymphadenopathy, reducing hepatosplenomegaly and increasing naive B cells.
What is the future of therapies in PID?
Advancements in gene editing (e.g., CRISPR) and pathway-specific inhibitors aim to provide personalized and safer treatments.
Why is pathway-targeted therapy preferred over broad immunosuppression in PID?
It allows precise correction of immune defects while avoiding excessive suppression of immune function, reducing side effects.
