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