Immunology Exam 1

commensal organisms

• enhance nutrition by digesting food and making vitamins

• protect against disease

• both species benefit

pathogen

any disease causing organism

opportunistic pathogen

a usually harmless organism that causes disease when the body’s defenses are weakened

DNA viruses

• chickenpox (herpesvirus)

• cold sores (herpesevirus)

• warts (papillomaviruses)

• sore throat (conjunctivitis)

skin epithelium

the body’s first defense against infection; can be damaged by wounds, burns, surgical procedures

mucus

thick fluid layer containing glycoproteins, proteoglycans, and enzymes that protect epithelial cells from damage and help to limit infection

cilia in respiratory tract

continually remove mucus, cleansing it of unwanted material including infectious organisms that have been breathed in

sebum

secreted by sebaceous glands associated with hair follicles; contains fatty acids and lactic acids, inhibiting bacterial growth on the skin

defensins

antimicrobial peptides that kill bacteria, fungi, and enveloped viruses

lysozyme

toxic enzyme in tears and saliva that kills bacteria by degrading their cell walls

innate immunity

determined entirely by the genes a person inherits from their parents

• recognize the pathogen

• recruit effector mechanisms

• response time=hours

• granulocytes and macrophages

effector cells

engulf bacteria, kill virally infected cells, attack protozoan parasites

complement system

battery of serum proteins that mark pathogens and attack them; circulate as inactive precursors; mostly synthesized in liver; main effect is to deposit large amounts of C3b on the surface of the pathogen to trigger its destruction by phagocytes which have complement receptors

inflammation

body response involving the recruitment of a number of white body cells (leukocytes) to infection of other bodily injury

• heat

• pain

• redness

• swelling

cytokines

soluble proteins that carry messages from cell to cell

• dilation and increased permeability of blood vessels

• migration of cells into tissue (neutrophils and monocytes)

adaptive/acquired immunity

• adapts to the nuances of the infecting pathogen

• extremely specific unlike innate immunity

• mounted by white blood cells called lymphocytes (T and B cells)

• antigen-specific receptors

• antibodies

• lasts for a lifetime

• response time=days

clonal selection

each naive lymphocyte bears antigen receptors of a single specificity; all are different; receptors must be occupies for cell activation; trained not to target us

clonal deletion

lymphocytes bearing receptors for self are removed before they can mature

clonal expansion

• Number of cells that can respond to any one antigen is small

• Lymphocyte must be activated to proliferate

• Initiated in draining lymphoid tissues where antigens are presented to naïve lymphocytes

• Naïve cell becomes a lymphoblast which divides to form clone of about 1000 identical daughter cells which differentiate into effector cells

• 4-5 days to complete

• Significant number persist to become basis of “immunological memory”

lymphocytes

differentiate into B or T cells and are responsible for adaptive immune responses

plasma cells

B lymphocytes that secrete antibodies

dendritic cells

phagocytes and antigen presenting cells

mast cells

allergic response (IgE receptor); histamine release

NK cells

lymphocytes that use perforin and granzymes to kill virus-infected cells and tumor cells and secrete cytokines; Type 1 immunity, cell-mediated cytotoxicity; provide an early response to virus infection

macrophages

mature form of monocytes; relatively long-lived; engulf and kill invaders; antigen presenting cells; 1st line of defense that induces inflammation and secrete cytokines and chemokines that activate other immune cells

eosinophils

phagocytic; handle larger parasites

basophils

not phagocytic; allergic responses and histamine release

megakaryocytes

giants cells that arise from multiple precursors and are permanently in bone marrow; produce platelets

neutrophil extracellular traps (NETs)

neutrophils throw “web” of DNA to attack bacteria may; trap microbes and expose them to antimicrobial molecules

Cytotoxic T cells

secrete cytokines and help B cells make antibodies

primary/central lymphoid tissues

lymphocytes develop and mature

secondary/peripheral lymphoid tissues

mature lymphocytes respond to invading pathogens

lymph node

• filter blood and produce extracellular fluid called lymph

• contains B and T lymphocytes in different zones

• B cells undergo intense proliferation in germinal centers of nodes after encountering antigen

• where B and T cells are activated

spleen

serves as filter for blood

• removes damaged or senescent RBCs (in red pulp)

• defends against blood-borne pathogens (in white pulp)

opsonization

coating a microbe with specific protein for facilitation of phagocytosis

• CR1 binds C3b

• CR3 and CR4 bind iC3b

lysis

perforation of pathogen cell membranes

alternative pathway

first to be activated; environment at the pathogen surface alters C3 conformation to resemble that of activated C3b; proceeds in the absence of specific antibody and leads to generation of a distinct C3 convertase called C3bBb; amplifies the other pathways by providing alternative C3 convertase that deposits more C3b molecules on pathogens

lectin pathway

second to be activated; mannose-binding lectin binds to pathogen surface and activates the complement cascade and production of C3b

• MASP-1 thought to cleave C2 and help activate MASP-2 (same as classical)

• MASP-2 cleaves C4 and C2 (same as classical)

• leads to formation of classical C3 convertase (C4bC2a)

classical pathway

last to be activated; C-reactive protein or antibody binds specific antigens on pathogen surface, activating the complement cascade and production of C3b

• C1q binds Fc region of antibodies IgG or IgM, or C-reactive protein

• activated C1s enzyme cleaves C4 then C2

• C4b and C2a form C4bC2a

membrane-attack complex (MAC)

the terminal components of the complement cascade comprise the C5, C6, C7, C8, and C9 proteins which form this

• C3b binds to C3 convertase to form C5 convertase

• alt C5 convertase (C3bC3bBb) cleaves C5 to C5b, C5a

• C5b initiates by making holes in membranes of pathogens and eukaryotic cells

• classical and lectin pathway C5 convertase is C4bC2aC3b

formation of C3 convertases

the point at which the 3 pathways of complement activation converge

DAF (decay accelerating factor) and MCP (membrane co-factor P)

ensure that C3b is deposited only on pathogen cell surface

Protectin (CD59)

inhibits formation of MAC by binding C5b678

C5b678

present on human cells to prevent complement from damaging them

properdin

upregulates alternative pathway which has positive effect on activation

Factors H and I (protease)

downregulate C3b which has negative effect on activation

C3a and C5a

anaphylatoxins that increase inflammation and cause anaphylactic shock

macrophage

become activated upon binding by microbe; these immediately recognize pathogens

Scavenger R

trigger phagocytosis, cell adhesion, intracellular signaling to identify microbes

• Mannose R (SR-E3)

• diction (SR-E2)

toll-like receptors 4 (TLR4)

recognize the lipopolysaccharide of gram-negative bacteria; signaling leads to activation of the transcription factor NFkB and synthesis of inflammatory cytokines

NFkB

complex that controls transcription; first responder to cellular harm; controls cytokine production; regulates cell survival

NEMO deficiency

lacks one of subunits of IKK —> No NFkB activation —> abnormal development of skin, teeth, hair, and bacterial infections

NOD 1 and 2

intracellular sensors of bacterial infections; soluble cytoplasmic receptors; detect products from the intracellular degradation of phagocytoses bacteria; complement membrane-bound TLRs

RIG-1 like receptors (RLRs)

they recognize viral nucleic acid which initiates interferon production

Type I interferon

initiates viral response in adaptive immunity

Type II interferons

interact with T-cells

apoptosis

cells dying in a controlled way

NLRP3

intracellular sensor that detects a broad range of microbial motifs, endogenous danger signals and environmental irritants, resulting in the formation and activation of pyrogen

pyroptosis

secretes IL-1B by an activated macrophage; faster than apoptosis; forms pores; less controlled

TNF-a

cytokine released by macrophages during infections as a result of TLR4 stimulation by LPS; induces blood vessels to be more permeable, enabling cells, fluid, and soluble effectors to enter infected tissue; induces inflammation; secreted by macrophages, NK cells, and T cells; beneficial if local; septic shock is systemic

IL-6

cytokine released by macrophages during infections; induces fat and muscle cells to metabolize, generate heat, and raise the temperature in infected tissue; induces inflammation

CXCL8

cytokine released by macrophages during infections; recruits neutrophils from the blood and directs them to the infected tissue; induces inflammation

CCL2

cytokine released by macrophages during infections; recruits monocytes from the blood and directs them to the infected tissue; induces inflammation

IL-12

cytokine released by macrophages during infections; recruits and activates natural killer cells to secrete cytokines that strengthen macrophages’ response to infection; induces inflammation

neutrophils

short-lived phagocytes with lots of granules used to kill bacteria; die in tissues after a few hours and form pus

granules

little vesicles with many toxins used to kill; can perform phagocytosis

Azurophilic (Primary) granules

proteins that disrupt and digest microbes (lysozyme, defensins, myeloperoxidase, cathepsin G, elastase). A negatively charged matrix of proteogylcans bind all the proteins

Specific Granules

unsaturated lactoferrin that competes with pathogens for iron and copper, lysozyme, etc

NADPH Oxidase

assembled when phagosome fuses with specific granules

respiratory burst

rapid release of reactive oxygen species (ROS) —> superoxide anion and hydrogen peroxide; Hydrogen peroxide is neutralized by catalase; if not controlled, can cause a lot of damage (needs to be deactivated)

neutrophil function

• degranulation

• NETosis

• ROS (reactive oxygen species production)

• phagocytosis

Chronic Granulomatous Disease (CGD)

• Genetic defect in NADPH Oxidase

• No respiratory burst. pH cannot be raised.

• Pathogens not killed

• Infected neutrophils phagocytosed by macrophages, but pathogens survive

• Huge granulomas formed full of infected neutrophils

C-reactive protein

initiates the classical pathway of complement activation

ILC1 (innate lymphoid cell)

Type 1 immunity, conventional inflammatory activation of macrophages

ILC2

Type 2 immunity, with noninflammatory activation of macrophages

ILC3

Type 3 immunity, promoting phagocytosis and secretion of antimicrobial peptides

Lymphoid-tissue inducer cell (LTi)

formation of secondary lymphoid structures

IgM

• first antibody made

• strong complement activation

• on naive BCRs

• 10 binding sites

IgD

• on naive BCRs

• role in B cell activation

IgG

• most abundant in serum

• opsonization, neutralization

• crosses placenta

• 2 binding sites

IgA

• mucosal immunity

• secreted in tears, saliva, breast milk, gut, lungs

• protects mucosal surfaces

IgE

• binds mast cells/basophils

• defense vs parasites

• allergy responses (itch)

antibody neutralization

blocks microbes/toxins

framework regions

regions between the hypervariable regions

hypervariable regions

• HV1, HV2, HV3

• where the antigen binds and sticks due to high diversity

combinatorial diversity

the combination of the heavy and light chain determines the final antigen specificity

antigenic determinant/epitope

structure recognized by an antibody

somatic recombination

point mutations in V regions after activation —> higher affinity; needs to recognize where to cut/bind

junctional diversity

imprecise joining adds/removes nucleotides at junctions

class switching

the constant region of the immunoglobin heavy chain changes but the variable regions do not, and therefore antigenic specificity remains the same

affinity

measure of strength which one molecule binds to another at a single binding site

avidity

the overall strength of binding of an antibody with multiple binding sites to an antigen