Inflammation and Immunity

Commensal organisms

Interact with humans harmlessly

Environmental organisms

Don’t interact with humans directly

Pathogens

Organisms that cause disease, organisms that interact with humans with negative effects

Function of the immune system

Distinguish self vs non self, dangerous vs benign

Self vs non self

Protect against infections and tumors but not autoimmunity

Dangerous vs benign

Response to pathogens but not to commensal organisms, food, etc

Hematopoietic stem cell gives rise to

Common lymphoid progenitor, common myeloid progenitor

Common myeloid progenitor derivative cells

Myeloid cells and dendritic cells

Myeloid cells

Neutrophils, eosinophils, basophils, mast cells, monocytes; called granulocytes, polymorphonuclear (PMN)

Monocytes

Differentiate into macrophages, only in the tisse

Common lymphoid progenitor derivative cells

T cells, B cells, NK cells, dendritic cells

Innate immune system

Immediate, doesn’t need time to develop

Adaptive immune system

Delayed response, takes time to build up antibodies

Innate immune system secreted molecules

Complement, defensins, lysozyme

Adaptive immune system secreted molecules

Antibodies, cytokines

Innate immune system uses

DNA encoded antigen receptors, all innate cells have same set of receptors, broadly specific, no memory

Adaptive immune system uses

DNA recombination for antigen receptors so that each T cell or B cell has its own unique receptor, finely specific and memory for infections/exposures

Neutrophil

40-60% of WBC, most common type

Monocyte

2-8% of WBCs, become macrophage in tissues

Macrophage

Only found in tissue, derived from monocytes

Neutrophils, monocytes, and macrophages are

Anti-bacterial, -fungal, and -parasitic

Natural killer (NK) cell

1-3% of WBCs, anti-viral

Eosinophil

1-6% of WBCs

Basophil

<1% of WBCs

Mast cell

Only found in tissue, like macrophage

Eosinophils, basophils, and mast cells are

Anti-helminth (worm parasites) and allergic response

T and B cells

Lymphocytes, 20-40% of WBCs

Dendritic cell

Antigen presenting cell, present in tissues and lymphoid organs, captures antigens and activates T cells

Adaptive immune cells are highly specific responses to

Any and all types of pathogens (bacteria, viruses, fungi, and parasites)

Cytokines

Small secreted proteins that control growth, function, activation of immune cells expressing apropriate cytokine receptor, communication between immune cells

Cytokine expression

Can be constitutive (constantly expressed) or inducible (selective expression)

Dendritic cells migrate

To lymph nodes to activate T cells

Complement

Soluble component of immune response, enhances inflammatory response

Chemokines

Subset of cytokines that induce chemotaxis, brings in leukocytes from activated capillary into infected tissue to mediate immune response and facilitate phagocytosis

Chemotaxis

Movement of cells across a chemical gradient, brings cells closer to source of secretion

Antigens and antigen presenting cells (APCs)

Drain from tissues to lymph nodes

Lymphocytes are activated in

Secondary lymphoid organs (lymph nodes, spleen)

T cells are activated by

Dendritic cells presenting antigens to CD4+ T cell and CD8+ T cell

CD4+ becomes

T helper cell (Th)

T helper cell (Th) function

Secrete cytokines, activate innate cells, activate B cells, anti-bacterial, -viral, -fungal, -parasitic

CD8+ becomes

Cytotoxic T lymphocytes (CTL)

Cytotoxic T lymphocytes (CTL) function

Kill infected cells, anti-viral

B cells are activated by

Soluble molecules or pathogen surfaces

B cell activation and function

Differentiate into plasma cells and produce antibodies, antibodies neutralize (prevent infection), activate innate cells, activate complement

B cell receptors

Bind soluble, free-floating or surface antigens

T cell receptors

Only bind small peptide antigens (8-20 amino acids long) presented on cell surface/brought by dendritic cells

Pathogen can be immediately recognized by innate immune system by

Activation of complement cascade or by pattern recognition receptors on macrophages

Pathogen Associated Molecular Patterns (PAMPs)

LPS (lipopolysaccharide), lipoproteins, lipoteichoic acid, peptidoglycan, flagellin, fungal sugars, unmethylated CpG DNA, dsRNA, viral ssRNA (uncapped)

Pattern recognition receptors (PRRs)

Bind to PAMPs, can be surface/extracellular (LPS, flagellin, peptidoglycan, lipoproteins), endosomal/intracellular (bacterial nucleic acids), or cytoplasmic (viral RNA/dsRNA)

Toll-like receptors (TLRs)

Recognize many PAMPs, hook shape

TLR4 recognizes

LPS to trigger cytokine response (kinase signaling cascade)

Inflammatory cytokines

Interleukin 1 (IL-1), tumor necrosis factor (TNF), interleukin 6 (IL-6), interleukin 8 (IL-8)

PRRs are expressed by

All WBCs, some other cells, to have broad specificity for introducing cytokines and chemokines

Inflammatory cytokines mediate

Endothelial cell activation, inflammation, and capillary vasodilation

Rapid response system to foreign pathogens

Complement proteins recognize pathogens, convert to active proteases and inhibit proteolytic cascade

Activated complement components functions

Active protease, induce lysis of pathogens directly, enhance phagocytosis of pathogens and increase inflammation by inducing vasodilation

Complement proteins baseline

Group of more than 30 inactive proteases in plasma and interstitial fluid

3 pathways of complement activation

Alternative pathway, lectin pathway, classical pathway

Alternative pathway

Complement activation by exposure to bacterial membranes, first to act (immediate)

Lectin pathway

Complement activation by mannose-binding lectin (MBL), induced by systemic inflammation (24-48 hrs after infection)

Classical pathway

Complement activation by antibodies, 5-7 days after 1st exposure but immediately after 2nd exposure (pre-existing antibodies)

All 3 pathways of complement activation form

A C3 convertase that cleaves C3 into C3a and C3b

Membrane attack complex (MAC)

Pokes holes in bacterial cells to lyse them, activated by C5 convertase

3 functions of complement

Bacteriolysis, opsonization, vasodilation

Opsonization

C3B/IgG subunits attach to pathogen surface for phagocytosis, coat surface for ease of attachment by phagocytes

C3a and C5a enhance

Inflammation by binding to endothelial cells and inducing vasodilation

Cleavage of C5 by C5 convertase

Recruits MAC for bacteriolysis

Inhibitory proteins protecting host membrane from complement

Factor H and Factor I, decay accelerating factor (DAF), membrane co-factor protein (MCP), CD59 (destabilizes MAC)

Endothelial cell activation causes

Vasodilation and inflammation due to gaps in tight junctions of local capillaries

Endothelial cell activation mediated by

Cytokines IL-1 and TNF along with C3a and C5a

Glycocalyx

Fuzzy gel like sticky layer made of proteins and sugars, heavily glycosylated surface molecules, cytokines increase expression

Glycocalyx adhesion molecules

Integrin, selectin, vascular addressin, immunoglobulin like molecule

Endothelial cells produce

CD8 chemokines to bind rolling neutrophils and induce expression of LFA-1

Leukocyte factor for adhesion 1 (LFA-1)

High affinity integrin, induces neutrophils to stop and squeeze between tight junctions into the tissue

Movement of neutrophils across capillaries

Transmigration, diapedesis, extravasation

Tissue alarm system

Brings in neutrophils and monocytes along chemokine gradient; macrophages, IL-1, TNF

First responders

Neutrophils, most abundant in inflamed tissue, brought in along chemokine gradient

Key functions of innate immune cells

Phagocytosis, degranulation, extracellular DNA traps, direct cytotoxicity

Phagocytosis

Phagocytes bind to pathogens using bacterial sugars, lipids, etc or opsonins (C3b, IgG), take up and degrade pathogens; engulfment of foreign particles into endosomal vesicles called phagosomes

Bacteria with capsules

Resistant to phagocytosis, require opsonins for phagocytosis and lysing

Phagolysosomes

Take up pathogens, fusion of phagosome and lysosome, acidic (pH 3.5-4), oxidative burst and nitrosative burst, enzymatic degradation of pathogens

Oxidative burst vs nitrosative burst

NADPH oxidase for oxidative burst makes reactive oxygen species, nitrosative burst makes nitric oxide (free radical)

Enzymatic degradation of pathogens

Lysozyme for bacterial wall degradation, proteases, lipases, nucleases

Degranulation of activated neutrophils

Neutrophils release granules - include lysozyme, myeloperoxidase, reactive oxygen species, leukotrienes, histamines

Neutrophil extracellular traps (NETs)

Release of DNA and histones from dying neutrophils, sticky matrix rich in antimicrobial molecules that trap and kill bacteria

Results of oxidative burst and degranulation

Toxic, causes activated neutrophils to die within 24 hours typically

Pus is composed of

Mostly dead neutrophils

Direct cytotoxicity through natural killer cells

Granules poke hole in target cell membrane, deliver molecules that induce apoptosis, activated by down-regulation of inhibitory ligands and expression of activating ligands in infected cell

Local inflammation mediated by

IL-1, IL-6, TNF, C5a

Local inflammation mediation

Activation of local immune cells, endothelial cells, vasodilation, leukocyte recruitment to tissue with chemotaxis

Systemic inflammation caused by

Cytokines in bloodstream distributed across the body, including capillary, G-CSF, GM-CSF, TNF, IL-1, IL-6

Systemic inflammation cause

Prolonged production of inflammatory cytokines leads to systemic distribution of cytokines in blood

Systemic inflammation short term effects

Release of neutrophils from BM, increased neutrophils in circulation, increased hemotopoiesis, production of new leukocytes

Systemic inflammation long term effects

Increased immature neutrophils (bands) in circulation, can cause fevers, rashes (vasodilation), acute phase response, sepsis, septic shock

Chronic inflammation associated pathologies

Autoimmune disease, cardiovascular disease, diabetes, obesity, immune dysfunction during aging, neurological diseases, tumorigenesis, inflammatory bowel disease (IBD)

Alternative and classical complement deficiencies

Susceptibility to encapsulated bacteria

Deficiencies in complement inhibitors

Overactive complement activation, paroxysmal nocturnal hemoglobinuria (PNH)

Deficiencies in pattern recognition

Defective TLR signaling, susceptibility to pyogenic bacteria

Defective oxidative burst in phagolysosomes

Chronic granulomatous disease (CGD), defective NADPH oxidase, susceptibility to bacterial and fungal infections

Defective lymphocyte trafficking

Leukocyte adhesion deficiency (LAD), loss of LFA-1, failure of WBCs to traffic into infected tissues, susceptibility to many bacterial infections