L2 Innate Immune System (macrophage)

Primary Lymphatic Organs

Bone marrow, thymus, fetal liver

(main job is develop+create immune cells)

Secondary lymphatic organs

Spleen, lymph nodes, lymph ducts, tonsils, adenoids (specialize and mature)

Lymphatic vessels

part of circulatory system; carry clear fluid (lymph) towards heart, transport immune cells

First Line of Immune Defense

Physical barriers (skin, mucus) and chemical barriers (pH, lipids, enzymes)

Second line defense

Innate immune system, nonspecific response (phagocytic cells, inflammatory response, NK cells, etc.)

Third Line of Immune Defense

Adaptive immune system; specific slower response; improved recognition/immunological memory- faster secondary response (B and T Cells)

Innate Immune System Cells

Phagocytes: monocyte/macrophages, neutrophils

Mast cells, eosinophils, basophils (Granulocytes) (for bacterias, release enzymes to kill)

NK cells, innate lymphoid cells

Adaptive Immunity Cells

Specific Antigen receptors, B Cells (Humoral) (antibodies), T cells (Cell mediated) (Lymphokines), NKT cells

Cell interactions of Immune System

Antigen leads to APC MP, combines with MP, and leads to activated MP. Leads to production/activation of T-helper cells, making TH1 (turn on more macrophage) and Th2 (Turn on B cells). T helpers also help turn on regulatory T or Killer T cells.

B Cells turned on by Th2 and Antigen, leading to sensitized B cells, and memory B cells. Sensitized B cells also turn into plasma cells that secrete antibodies

B cells and killer T cells are regulated.

Origin and Development of Immune Cells (Bone Marrow, Blood, Tissue)

In the bone marrow Stem cells turn into progenitor cells (Common lymphoid or Common Myeloid progenitor) that are committed in specialization and dividing

CMP turn to myeloid and then granulocyte in bone marrow while CLP turns into lymphoid in bone marrow.

Through thymus lymphoid cells turn into either T cells (90%) or B cells (10%) live in the blood. Granulocyte specializes in blood into PMN (neutrophils 70), eosinophil (<2), and basophils (<3). Myeloid also turn into monocytes here

T cells go into tissue when cell mediated while B cells turn into B cells living in the tissue for humoral immunity as memory

Basophils turn into mast cells to cause inflammatory reaction.

Monocyte become macrophage in tissue

Innate Immune System Functions

Nonspecific Defense: Doesn't require specific antigen receptors/no prior learning

Provides barriers (physical, mechanical, chemical, cellular)

Identify and eliminate pathogens + other foreign bodies

initiate inflammatory response

Activate specific immune responses (macrophages)

Neutrophils/PMN (Presence, lifespan, functions)

60-70% of WBC, present in tissue at low levels (increase following injury/infection)

9-12 hour life span

First cell at site of infection/injury

Ingest+kill microbes and foreign materials; involves PAMPs (for nonsterile infections) and DAMPs (for sterile inflammatory response) that bind to PRRs

Mononuclear phagocytes (presence, lifespan) +Types of macrophage

1-6 % WBC (MONOCYTES), in tissue is macrophages

Resident macrophage- throughout body, largest population in liver and lung; come from embryonic origins

Inflammatory macrophage: response to injury and infection; come from bone marrow

Life for a very long time

Function of Macrophage

Identify+eliminate pathogens. Has PRR activated by PAMP/DAMP; scavenger receptors; use phagocytosis, pathogen destruction or isolation

Regulate inflammatory response, initiate would healing and promote angiogenesis

Maintain homeostasis; lipid and iron metabolism

Major secretory activity

Activate adaptive immunity (APC+Th Cell activation)

Tumor surveillance and cytotoxicity

Macrophage plascitity

Macrophage modify phenotype/reprogram based on pathophysiologic conditions.

M1-M2 reprogramming help with inflammation resolution and wound repair

Inflammation

response of vasularized tissue to injury/infection, brings defense and healing mechanisms to site of injury

Neutralizes/destroys offending agent, restricts tissue damage to small area, and alerts body to repair/heal

Acute Inflammatory Response (initial+secondary)

Short term response

initial is proinflammatory/cytotoxic caused by neutrophils+m1 macrophage accumulation, release mediators to destroy pathogen+increase inflammatory cells (call in neutrophils)

Secondary: anti/wound repair

M2 macrophage accumulate and release mediators to surpress inflammation + promote wound repair

How to resolve inflammation+wound repair?

Neutrophils undergo apoptosis

Proresolving mediators (lipoxins, resolvins, protectins) released to stimulate M2 efferocytosis/clean up of apoptic dead cells

M2 release mediators to down regulate inflammation (IL1-10, 4, 13)and promote wound repair and angiogenesis (TGFb, EGF, VEGF)

Release chemokines to stimulate fibroblast emigration to inflamed sites, produce ECM proteins

Inflammation Resolution failure

Chronic inflammation, foreign body response, granulomas, cancer

Chemotaxis

Migration to injured/infected site caused by chemotactic factors (Complement, fMLP)

How to remove/localize foreign bodies

Chemotaxis, phagocytosis, metabolic destruction, isolation of foreign body

Foreign Body Reaction

Macrophage wall off body if can't destroy it. Macrophage will fuse into giant cells, recruit other cells like PMN, lymphocytes, eosinophils, fibroblasts, form fibrous capsule around foreign body

FBR depends on size, structure, and surface character of FB.

Granulomas can lead to chronic inflammatory response

Macrophage Secretory Function (3 things)

Release degrading enzymes for ECM proteins (collagenase, elastase)

Release host defense enzymes ROS, RNS, protease, eicosanoids for host defense

Release regulatory proteins like cytokines/chemokines/growth factors/lipids

Immune Function of Macrophage

Antigen processing/presentation

Tumor Cytotoxicity

Tumor surveillance

Macrophage Antigen Processing

Phagocytosis of antigen, degradation/unfolding, bind to MHC II protein on APC, re express processed antigen together with MHC II, present to T-helper cells

NK Cells

Type of cytotoxic lymphocyte part of innate immune system

Apoptosis mediated by granules of perforin+granzyme, comes from CLP

ILC/Innate Lymphoid Cells

Three subsets + interleukins produced

Derived from CLP, is innate, analogous to helper T cells and cytotoxic NK cells (regulate homeostasis and inflammation)

Subsets defined by cytokines:

ILC1: weakly cytotoxi, produce TNFa and IFNg

ILC2: produce IL(interleukin) 4, 5, 9, 13: type 2 cytokines

ILC3: Produce IL 17+22

M1 vs M2 Macrophage

both come from bone marrow m0 macrophage

M1: Cytotoxic/proinflammatory; stimulate immune system (neutrophils)

M2: Anti-inflammatory/wound repair, has four subsets

a: Type II inflammation+Allergy+ killing parasites

b: Th2 Activation (Lead to B cell activation)

c: Immunoregulation, matrix deposition, tissue remodeling

d: cell cycle regulation