what is immunological tolerance?
the layers of protection imposed by the immune system to prevent the reaction of its cells and antibodies against host components
what are the four factors that influence immunological tolerance?
persistence
portal of entry; location
presence of adjuvants
properties of APCs
what is antigen sequestration/segregation?
the process of hiding an antigen from the immune system, typically by isolating it behind physical barriers or within specific compartments, to prevent an immune response
what is central tolerance?
deletion of 'self-reactive' lymphocytes within primary lymphoid organs
how does it work in the thymus?
negative T cell selection, T(REG) production
what happens when central tolerance is disrupted?
APECED/APS-1
genetic deficiency in AIRE
TH17 cells
TH17 cells
IL-17A
Il-17F
Il-22
what is clonal helplessness?
a mechanism of peripheral tolerance where T cells that encounter their specific antigen in the absence of adequate "help" from CD4+ T cells are unable to develop full, long-lasting function or memory and eventually undergo cell death
what is antigen sequestration/immune privilege?
the partitioning of various self-antigens away from immune mediators
if they're not exposed to each other, they're not likely to be reactive
this can be problematic, however, particularly in cases of trauma, the eye, or perhaps CTE
what is peripheral anergy?
a state of immune system unresponsiveness in which a lymphocyte, like a T-cell is unable to respond to an antigen even though it is present
a T cell needs two signals to activate
when T cells encounter a self-antigen without the second co-stimulatory signal
how do T(REG)s work?
cytokine deprivation
inhibitory cytokines
inhibiting antigen-presenting cells
cytotoxicity
T(REG)s are known to be: CD4+, CD25+, FoxP3
how does disruption of T(REG)s work?
immune dysregulation, polyendocrinopathy, enteropathy, x-linked syndrome
monogenic, impacts multiple organs, and displays significant immunopathologies
caused by a mutation in FoxP3
regulatory CD8+ T cells
generated in the periphery; act similarly to CD4+ T regs
regulatory B cells
inhibits adaptive immune responses with IL-10 secretion
regulatory DCs
IL-10 secretion
myeloid-derived suppressor cells
contact-independent suppression mechanisms that also suppress in cases of sepsis, trauma, or cancer
what is clonal deviation?
remember that the correct differentiation of T cell subset depends on the polarizing cytokines present at the time of differentiation
an immune system process where immature self-reactive T cells that would normally be eliminated by clonal deletion are instead diverted to an alternative differentiation pathway
type I response
intracellular pathogens inducing cell-mediated immunity
type II response
pathogens inducing humoral immunity particularly extracellular parasites
what is activation-induced cell death (AICD)?
repeated stimulation leads to cell death by mitochondrial (intrinsic) or death receptor (extrinsic) pathways
mechanism of apoptosis is usually through Fas/FasL interaction
what is linkage disequilibrium?
the non-random association of alleles at different loci
how does sex play a role in autoimmunity?
in general, women are more resistant to infection, but more prone to autoimmunity
in general, men are more susceptible to infection and cancer, but have more tolerance for self-antigens
what are other potential genetic factors?
race
age
sex
what are environmental factors?
diet, geographic location, presence of infection
what is molecular mimicry?
a phenomenon where a foreign antigen from an infectious agent closely resembles a host's own protein or antigen, causing the immune system to mistakenly attack its own body tissue
what is bystander activation?
an immunological process where immune cells, like T cells, are activated by cytokines released during an infection, even if they are not specific to the infecting pathogen
what are other potential mechanistic causes of autoimmunity?
new exposure of self-antigen
insufficient clearance of dead cells
self-antigen modification
what is epitope spreading?
a process where the immune response expands beyond the initial target epitope to include additional epitopes on the same or different antigens
types of local immunity
hashimoto's thyroiditis
type I diabetes
myasthenia gravis
multiple sclerosis
types of systemic autoimmunity
systemic lupus erythematosus
rheumatoid arthritis
what are the differences between antibody-mediated immunity (type II), immune complex-mediated autoimmunity (type III), and type IV
type II uses antibodies to attack cell surfaces, type III forms circulating immune complexes that deposit in tissues, and type IV relies on T cell activation to cause inflammation and damage
what are the potential treatments and/or therapies for autoimmunity?
immunosuppression can be broad-spectrum or target-specific
rituximab depletes CD20+ B cells to diminish the pool of cells producing autoreactive antibodies
stains lower C-reactive protein, biomarker of inflammation, and reduce pro-inflammatory cytokines
abatacept is a CTLA-4/Fc fusion protein that blocks CD28 from CD80/CD86
what is IVIG?
intravenous immunoglobulin
what are the functions of IVIG?
saturating Fc receptors and inhibiting receptor-mediated phagocytosis
saturating FcRn, it inhibits IgG recycling, reduces half life in the blood
upregulates expression of inhibitory FcyRIIB to further inhibit phagocytosis