Immunity 

Immune Response

Immunity = body's defense against invading microbes preventing damage

Immune Response = body's rxn to foreign obj in body, tissue injury, malignant cell transfrmtion, cell death.

INNATE components

Preventing microbes from entering the body

-PHYSICAL BARRIER

-MECHANICAL REMOVAL

-CHEMICAL MICROBICIDE

-BIOLOGICAL MICROBICIDE

-COMMENSAL/MUTUAL EXISTENCE

INNATE components

destroy microbes in body on first encounter

Natural Killer cells (NK cells)

Neutrophils

Macrophages

INNATE 

sebacceous glands [biological microbicide]

secrete sebum(made of fat and wax)=push bacteria & debris out ...acidity retards bacterial growth

-mucous membrane & hair = trap& remove microbes out(sneezing)

-Cilia lining of Trachea (lungs) = outwards movements, coughing(removes microbes)

-FLushing/washing = sterile acidic urine

Chemical Microbicide

Biological Microbicide

Chemical Microbicide = stomach acid (pH 1.5-3.5)

Biological Microbicide = Lysozyme 

[in saliva, sweat, human milk, mucus,neutrophils;rice,eggwhites]

[breaks dwn cell wall]

[used as preservative]

Commensal Microbes

Gut flora

vs

Vaginal Flora

Gut flora:

10^14 gut bacteria lining mucosa compete w/ harmful microbes for nutrients and GI attachmnt

Vaginal Flora: 

mostly lactic-acid producers, pH <4.5 [unfavorable env for pathogenic microbes]

Cell Player Origins

NEUTROPHILS[phagocyte]

MACROPHAGE[phagocyte]

NATURAL KILLER CELL

pluripotent stem>myelloid>granulocyte CFU>NEUTROPHILS 

pluripot>myeloid stem>moocyte CFU>Monoblast>>monocyte>MACROPHAGE

pluri>lymphoid>NK progenitor>NATURAL KILLER CELL

WBCs

[NLMBE]

NEUTROPHILS

LYMPHOCYTES

MONOCYTES

BASOPHILS

EOSINOPHILS

WBCs [NLMBE]

RBC 

PLATELETS

HEMATOCRIT [Hct]:packed rbc volume

HEMOGLOBIN [Hgb]

NEUTROPHILS [MARROW,BLOOD,TISSUE]

(circ neutrophils apoptose after<24 hrs....)

(also cleared by phagocytosis by macrophages in liver, spleen, and bone marrow)

-FROM PROGENITOR CELLS IN BONE

-EQUILIBRATING[1TO1], MARGINAL [adhered to bld vessls], CIRCULATING NEUTROPHILS [free]

-CIRCULATING NEUTROPHILS [infiltrate tissue in response to signals from tissue macrophages]

-phagocytose/kill microbes in tissue using toxic factors in their granules

Neutrophil infiltration

1. macrophage recognize bac in tissue/..get activated & release TNFalpha and IL-1B and PAF

2.PAF inc surfaceinc surf expression of endothelial P-SELECTION (CD62P/E) that interacts w/ its ligand CD15s on free flowing neutrophil to capture them via transient ,low affinity binding

3. Neutrophil CD62L interxn w/ CD34 and GlyCAM-1 cause captured neutrophils to roll

4. Cytokines TNFalpha & IL-1B over 1 to 6 hrs induce surface expressionof CD54(ICAM-1) & CD102(ICAM-2)

and CD18/CD11a,b in endothel cells & neutrphls

5. response to chemoattractants=neutrophils extend pseudopods and CD31:CD31 (PECAM-1) interxns help pull neutrophils thru

6.once in subendothelial matrix, neutrophils secrete protease to digest matrix protein &move to infctn

7. chemotactic agents attract neutrophil to site of infctn:

N-formyl peptides from bac, complements such as C5a, lipids such as PAF, and chemokines such as IL-8

-inc by 5x or more

-Shift neutrophilia = dec marg pool, inc circ pool, no change in total pool, no in cin band cells.---transient---can be due to vigorous exercise, epinephrine injection and seizures

-True Neutrophilia = indicative of infctn or inflmtn; circ pool dec initially then inc markedly w/ inc band cells in blood ['left shift']

Nuetropenia (dec)

[inc risk of bac and viral infctns]

-when <1000-1500/mm³ (from 4,500/mm³)

-genetic(ELA2)

-acquired

(inctn:bacteria&viruses)

(drug-indiced:antithyroid meds,cv drugs[quinidine] form immune complex to attach to neutrophil for its destruction;chemodrugs r directly toxic to progenitor cells)

-autoimmune:anti-neutrophil antibody as main mechanism

-pattern recognition receptors

-proteins encoded by ~1000 genes/recognize major microbial proteins,carbs,nucleic acids

-

-pathogen associated molecular patterns of microbes

-highly conserved structureessential for surviaval of microbes 

-mutation or reduction in production of conserved proteins is lethal to the microbes

TLR[toll-like receptors]= identified in fruit fly.protects from lethal fungal infctns

MBL[mannan-binding lectin]= MBP recognizes bac polymannose that is not present on human cells

sigalling pathway>>> 

-LPS:LPB

-CD14: non transmembrane protein

-adaptor protein: MyD88

-Kinase:MAPK(mitogen activated protein kinase)

-AP-1,NF-kB: gene transcriptional factors

Complement system 

-proteins in circulatn activated by microbes

-3 actvtn pathways(ALL LEAD TO C3a & C3b activatn)

lectin:MBL recognizes microbe surface

classical:IgM/IgG binds microbe and interacts w/ C1q

alternative:direct intrxn of C3 w/ microbial surface

-C3b-C4a-C2b converts C5 to C5a and C5b

-C5b complexes w/ C6-9 to form MAC to lyse microbe

-C3b opsonizes microbe for neutrophil (C3R) phagocytosis

-C3a & C5a are chemoatractant for neutrophils

- derived from monocytes in blood which derived from bone marrow progenitor cells

-recognize & phagocytose pathogens

-detect tissue injury/remove damaged cells 

-recruit neutrophils & monocytes to the site of infection/damage

Dendritic cells 

-as macrophages

[in skin/lining ofnose, lungs, and GI=major antigen processing cells (APCs) in adaptive immunity]

-macrophages in bone marrow clear improperly formed cells & release cytokines to stimulate maturation of hematopoietic cells

-spleen red pulp Macrophages clear senescent RBCs

-Microglia are resident immune cells in CNS

-microbe recognized using TLRs

-tissue macrophage get activated & release variety of soluble factors to influence func of other cells

-chemokines recruit aditional monocytes to site of infection which differentiate into inflammatory macrophages to help microbe clearance

Macrophage & apoptotic cell

[TIM4=T-cell immunoglobulin and mucin domain-containing molecule-4]

-macrophage can recognize apoptotic cell in body to remove it

-normal cells have few Phosphatydlserin molecules (PS) in outer leaflet membrane

-in apoptosis: PS molecules flipfrom IN to OUTTER leaflet

-macrophages us surface receptor TIM4 to recognize PS on apoptotic cells

NK cells[natural killer cells]

-can be activated b IL-12 secreted by activated macrophages

-IL-12 activated NK cells produce interferon-gamma (IFNγ) to enhance macrophage phagocytosis of microbes

-5-15% of lymphocytes

-widely distributed (lung,liver,spleen,gut,bone marrow,uterus)

-granules contain perforin & granzymes to kill recognized cells

-detect changes in surface molecule expression pattern induced by viruses or malignant transformation

-proteins insert into and assemble a pore in target cells' plasma membrane

-formed in cell

-cysteine protease

-enters target cell through the perforin pore

a.cleaves pro-caspase-3 to activate caspase-3 that degrades nuclear lamins and activates PARP[poly-ADP ribose polymerase], a DNA damage repair enzyme

b.cleaves Bid to cause mitochondria to release Cytochrome C that activates caspase-9 that in turn activates more caspase-3...results in eventual cell death