04: immunology

immune memory

• conferred by the acquired immune system through the generation of memory T-cells and B-cells from the first encounter

• second encounter with the same pathogen will lead to a response with greater magnitude and with faster kinetics

innate immunity

• rapid but short-term response to acute insult

• non-antigen specific

neutrophils

ingest and destroy

eosinophils

release toxic molecules and destroy

monocytes/macrophages

ingest, destroy, and present antigens

natural killer cells

kill cancer or viral infected host cells

basophils/mast cells

release first chemicals that start inflammation

dendritic cells

ingest, recruit other cells, and present antigens

microglial cells

brain-specific monocytes

alveolar macrophages

lung-specific monocytes

Kupffer cells

liver-specific monocytes

mesangial phagocytes

kidney-specific monocytes

synovial A cells

joint-specific monocytes

adaptive (acquired) immunity

• activated by, and responds to, innate immunity

• specialized and adaptable

• mediated by T- and B-lymphocytes, with help from APCs

T-cells

• produced in bone marrow but mature in thymus

• activity against infected host cells (inaccessible to antibodies)

helper T-cells

assist other immune cells with maturation/activation

cytotoxic T-cells

identify and destroy virally infected cells and tumor cells

regulatory T-cells

suppress and regulate auto-reactive T-cells

T-cell receptor (TCR)

• consists of an alpha and beta chain

• each subunit is generated through recombination of 1 segment each from the V and J loci (alpha) and V, D, and J loci (beta)

• different combinations of subunits recognize different antigens

B-cells

• form and mature in bone marrow

• each lymphocyte produces only one type of antigen receptor

plasma cells

produce antibodies

B-cell receptor (BCR)

• membrane-bound form of the antibody that recognizes one antigen

• two identical binding sites on each fork of the Y

• can bind to antigens directly in the absence of co-receptors

inflammation

• acute (immediate) response to tissue injury and immune activation

• crosstalk and signaling through the release of cytokines and inflammatory chemicals/hormones

immunotherapy

specific medical treatments that use a person’s immune system to fight diseases

vaccines

• biological products that can be used to safely induce an immune response that confers immune protection against infection and/or disease on subsequent exposure to a pathogen

• contain antigens that are either derived from the pathogen or produced synthetically to represent components of the pathogen

immune checkpoint inhibitors

take the ‘brakes’ off the immune system, which helps it recognize and attack cancer cells

oncolytic viruses

genetically engineered or naturally existing viruses that can selectively kill tumor or abnormal cells by infecting them to elicit an immune response, without damaging the healthy cells

monoclonal antibodies

recognize and bind to specific parts of a target to block its normal function and/or recruit other immune components to attack it

CAR-T

T-cells (collected from individual patients) genetically engineered to express tumor-specific “chimeric antigen receptors” on their cell surface

programmed cell death protein-1 (PD-1)

• produced on T-cell surfaces after prolonged T-cell activation

• binding to PD-L1 or L2 in target cells induces T-cell apoptosis

• down regulation of T-cell function

immunoglobulins

family of globular proteins (Ig), bind with specificity and affinity to antigens

constant region

• stem of monomer and lower part of Y

• Fc region is recognized by Fc receptors on leukocytes/complement factors

• μ, γ, α, ε, δ chains give rise to IgM, IgG, IgA, IgE, IgD

variable region

• two identical regions on the Y arms

• Fab-binding sites bind to antigens

• highly variable across antibodies

conjugated monoclonal antibodies

• mAbs joined to a chemotherapy drug, toxin, nucleic acid therapy, or radioactive particle

• take these cytotoxic substances directly to the cancer cells

• reduce the compounds’ damage to normal cells in other parts of the body

bispecific monoclonal antibodies

• 2 different mAbs are joined together and can attach to 2 different proteins at the same time

• one mAb is attached to tumor antigen, while the other attaches to T cells

• brings the cancer cells and immune cells together, which is thought to help T-cell response against the cancer cells

first generation CAR-T cells

• composed of single-chain variable fragment (scFv) from an antibody fused with the activating domains of CD3ζ

• induced a cytolytic response but were unable to produce cytokines or undergo expansion

second generation CAR-T cells

• incorporated costimulatory molecules such as CD28, 4-1BB, DAP10, OX40, or ICOS

• capable of cytokine secretion and continued expansion with repeated antigen exposure

third generation CAR-T cells

• use a “triple-decker” structure that couples two costimulatory receptor cytoplasmic domains with the activating domain of CD3ζ

• induced a stronger response

fourth generation CAR-T cells

combine the properties of the second-generation CARs with recombinant cytokine secretion