MICR 270 Module 1

Commensal

microorganisms that are harmless or beneficial, makes up most of our microbiome

pathogenic

microorganisms that can cause a disease state, make up less of the microbiome

Immune system

organization of cells, tissues and organs within the body that each have their own specialized role in defending against infection

• Includes innate and adaptive immune system

Immune response

reaction of immune cells to the presence and actions of microbes or danger signals in the body

What are the 2 functions of the immune system?

• Discriminate: recognize self from non-self

• Eliminate: destroy non-self (pathogen) and altered self cells (cancer)

What are the 2 possible dysfunctions of the immune system?

• Autoimmunity and hypersensitivity: misdirect or overly active immune system (ex; allergies)

• Immunodeficiency: underactive immune system (ex; AIDS)

Antigen

foreign protein that induces an immune response, typically including the production of antibodies. (antigen = antibody generator)

Antibody

protein that is produced in response to, and countering, a specific antigen

• Antibodies bind to foreign substances (antigens) in the body and provide a signal for their elimination

What is the most important property of the immune system?

• Balance is the most important property for the immune system

  • We don’t want an under or over functioning immune system

Lymphatic system

network of vessels that drain lymph fluid that filtrated from the capillary blood into the interstitial space

• often considered part of the circulatory system, but also important in immunity

Lymph

a colourless fluid containing white blood cells that bathes the tissues and drains through the lymphatic system into the bloodstream

• B cells and T cells (lymphocytes) are most commonly found in the lymph

Interstitial space

fluid filled areas that surround the cells of a given tissue

Circulatory system

where the lymph comes from and goes after being filtered

Lymphatic vessels

Distributed throughout the body and pick up lymph and carry it towards the heart where it can re-enter the circulatory system. Contain lymph nodes.

Bone marrow structure

• Flexible tissue

• Divided in two types: yellow and red marrow

• Filled with hematopoietic cells

Bone marrow function

• Red marrow

  • Importance for the immune system

  • Site of hematopoiesis

  • Site of B-cell development

• Yellow marrow

  • Some leukocyte development

  • Produces fat and cartilage

Bone marrow location

• Central cavity inside the bones

Hematopoietic

cells lodged within bone marrow responsible for producing the cells which circulate in the blood (RBC, WBC, platelets)

Hematopoiesis

the formation and differentiation of blood cells. Origin of all immune cells.

• Divided into myeloid and lymphoid

• Every immune cell originates from pluripotent hematopoietic stem cells in the fetal liver and bone marrow

Lymph nodes structure

• Small (1-25mm)

• Bean-shaped

• Numerous (~600)

• Divided into 3 regions (cortex, paracortex, and medulla)

• Filled with lymphocytes, macrophages and dendritic cells

Lymph nodes function

• Filters the lymph

• Often the first organized lymphoid structure that foreign molecules encounter when entering the body

Lymph nodes location

• Grouped along the lymphatic vessels

Lymphocytes

white blood cells which arise from the lymphoid progenitor lineage during hematopoiesis. Generally refers to B- and T-cells 

MALT (mucosal associated lymphoid tissue) structure

• Combined surface area of various areas in the body including BALT, GALT, lamina propria of intestinal villi, peyer’s patches, tonsils, appendix

• Filled with various types of immune cells depending on the location

MALT function

• Initiates immune responses to specific antigens encountered along all mucosal surfaces

MALT location

• Mucous membranes lining the digestive, respiratory, and urogenital systems

BALT

bronchus-associated lymphoid tissue; lymphoid structure part of the MALT located in lungs and bronchus

GALT

gut-associated lymphoid tissue; lymphoid structure part of the MALT located in the gut

lamina propria of intestinal villi

thin layer of connective tissue rich in immune cells located in the lumen of the small intestine

Peyer’s patches

small masses of lymphatic tissue found throughout the ileum region of the small intestine

Tonsils

collection of lymphoid tissue facing the aerodigestive tract, mainly located into the pharynx

Appendix

small pouch-like sac of tissues located in the first part of the colon in the lower-right abdomen. Harbours bacteria and helps with immune function. Plays a role in establishing the core gut microbiome.

Spleen structure

• Large, ovoid

• Divided into two compartments: white pulp and red pulp

  • White pulp is filled with macrophages, lymphocytes, T-cells, B-cells, and red blood cells (more important for immune system)

  • Red pulp is composed of cords of billroth and splenic sinuses filled with blood

Billroth

fibrils and connective tissue cells with a large population of monocytes and macrophages

Spleen function

• Red pulp filters the blood

• White pulp is the site of development of immune responses against antigens found in the bloodstream

Spleen location

Left abdominal cavity

Thymus structure

• Flat

• Bi-lobed; each lobe is divided into lobules which are organized each into two compartments (cortex and medulla)

• Filled with thymocytes, epithelial cells, dendritic cells, and macrophages

Thymus function

• site of T-cell development and maturation

Thymus location

• Situated above the heart

Thymocytes

T-cells found in the thymus

Primary vs secondary lymphoid organs

Discrimination in the immune system

ability of immune cells to distinguish between self and non-self components

MHC I

Major histocompatibility complex Class 1: a molecule on the surface of almost every nucleated cell in the body that presents a sample of the proteins found inside the cell

MHC II

class of MHC molecules present on special cells of the immune system (macrophages, dendrites, B-cells) essential for adaptive immunity to recognize foreign molecules

Elimination, and steps

abilities of immune cells to initiate an immune response. Steps:

Innate immune system

consists of physical, soluble, and cellular barriers that are scattered throughout the body to prevent the entry of any infectious agent and respond non-specifically

• Components:

  • First line of defence against foreign agents

  • Physical, soluble, and cellular barriers

• Functions:

  • Immediate recognition and response to invading pathogens (minutes or hours)

  • Recognizes general patterns not specific for any one antigen; limits the type of immune response initiated

Adaptive immune system

consists of cells and soluble components capable of recognizing and responding to specific pathogens

• Components 

  • Further divided into antibody-mediated humoral immunity (mediated by B-cell) and cell-mediated immunity (mediated by T-cell)

• Functions 

  • Longer time required to initiate a response to invading pathogens (days)

  • Recognize and responds to specific antigens - wider range of responses possible

  • Leads to immunological memory - quick response upon second infection

Amebocyte

a mobile cell (moving like an amoeba by pseudopodia) in the body of invertebrates

• Oldest cell to have given rise to a part of the immune system (phagocyte)

Pseudopodia

temporary cytoplasm-filled projections of the cell membrane that extend from motile and phagocytosing cells, usually used for motility or ingestion of extracellular components

Phagocytosis

the ingestion of bacteria or other material by phagocytes and amoeboid protozoans

Parsimony

the explanation requiring the fewest assumptions is most likely to be correct, the simplest explanation tends to be the right one

Evolution of the immune system

• Almost all vertebrates have GALT

• Most vertebrates have some sort of thymus or spleen

• Not many vertebrates generate lymphocytes in the bone marrow 

  • Sharks and rays are the earliest organisms with B- and T-cells 

• Not all vertebrates have lymph nodes (they are a more recent evolutionary trait)

• Innate immune systems are found in vertebrates, invertebrates, fruit flies and plants

• Adaptive immune systems are only found in subphylum vertebrata (all animals with backbones)

  • Only more complex organisms within this subphylum have well-developed adaptive immune systems

  • B-cells and T-cells are only found in jawed vertebrates

Immune system and pregnancy

Immune system is in a state of ‘flux’ (constantly changing) during pregnancy since the baby is 50% foreign DNA

• At the beginning many immune cells are recruited to the site of implantation to help with implantation (NK cells, neutrophils, T-cells)

• After 12 weeks, the immune system enters a state of immune ‘dampening’

• At end of term, immune system changes and is less inflammatory

Pluripotent

cells capable of giving rise to several different cell types

How do B and T cells mature?

• B cells reach maturity in bone marrow

• T cells travel further to the thymus to complete development 

Hematopoietic stem cell (HSC)

every blood cell arises from this, including erythrocytes (RBC), platelets, and leukocytes (WBC). Characteristics:

• Self renewal: ability to divide itself to replace older cells, keeping stem cell pool constant

• Pluripotent: ability to differentiate into several cell types. Once a stem cell commits to a lineage, it loses the ability of self-renewal and becomes a myeloid or lymphoid progenitor cell

Myeloid lineage

myeloid progenitor cells differentiate into most of the cells of the innate immune system

Myeloid progenitor cells

ability to differentiate into four different groups of myeloid cells, majorly innate immune system cells. 

• Granulocyte

  • Neutrophil

  • Eosinophil

  • Basophil

  • Mast cell

• Monocyte

  • Macrophage

• Erythrocyte (red blood cell)

• Thrombocyte (platelet)

Platelets

central contributor to the process of coagulation, wound healing, and fibrinolysis

• Have inflammatory functions that influence innate and adaptive immune response

• Intervene against microbial threats

• Recruit and promote innate effector cell functions

• Moderate antigen presentation

• Enhance adaptive immune responses

Monocytes

type of phagocyte located in the blood that are able to travel outside of the circulatory system by moving across the blood vessel walls. When they penetrate tissue they become macrophages and undergo changes:

• Get bigger

• Increase of number and complexity of intracellular structures (pseudopodia, phagosome, lysosome)

• Acquire better phagocytic abilities

Phagosome

vacuole in the cytoplasm of a cell containing phagocytosed particles enclosed within a part of the cell membrane

Lysosome

vacuole containing enzymes that digest particles; when fused with a phagosome it is called a phagolysosome

Granulocytes

group of WBC characterized by secretory granules in their cytoplasm

Mast cells

AKA granulocytes: located in the tissues with large granules containing histamine and other active substances. Function similar to basophil and are involved in allergy development.

Neutrophil

Abundant leukocyte that has characteristics of granulocytes and phagocytes

• Granulocyte characteristics: have a polymorphic nucleus and granules containing lytic enzymes (peroxidase, lysozyme, etc) which aid in infectious agent elimination 

• Phagocytic characteristics: have the ability to engulf and absorb (kill) bacteria

• Neutrophil are first to arrive at inflammation site 

• Lifespan of a few days

Polymorphic nucleus

a cell nucleus that assumes an irregular form or splits into completely separated lobes

Peroxidase

enzyme that catalyzes the oxidation of substrates by hydrogen peroxidase

Lysozyme

an enzyme that catalyzes the destruction of the cell walls of certain bacteria

Basophil

non-phagocytic granulocytes with the largest granules and least common type of granulocyte.

• Granulocyte characteristics: polymorphic nucleus, granules containing active substances (heparin, histamine)

• Function similar to mast cells (allergy development)

Heparin

a compound that inhibits coagulation

Eosinophil

phagocytic granulocytes

• Granulocyte characteristic: polymorphic nucleus, granules able to damage parasitic membranes

• Phagocytic characteristic: very minor role

• Play a role in defence against multicellular parasites like helminths

Lymphoid lineage

lymphoid progenitor cells differentiate into the cells that make up most of the adaptive immune system (lymphocytes; B and T-cells)

Lymphoid progenitor cells

ability to differentiate into two major type of cells of adaptive immune system (B and T-cells) as well as Natural Killer cells

• B-cell

  • Plasmocyte (effector B-cell)

  • Memory B-cell

• T-cell

  • Helper T-cell (CD4+ T cell)

  • Cytotoxic T-cell (CD8+ T cell)

  • Memory T-cell

Natural killer cells (NK cells)

granular lymphocytes with granules which contain perforin and granzymes

• Ability to recognize tumour or virus-infected cells despite lacking antigen-specific receptors (distinguish abnormal cells and destroy them)

• Exception for lymphoids because they do innate immunity

Perforin

a protein released by cytoplasmic granules that destroys target cells by creating lesions like pores in their membranes

Granzymes

proteases released by cytoplasmic granules that induce programmed cell death in the target cells

T-cells (T lymphocytes)

non phagocytic cells that have specific receptors at their cell surface called T-cell receptors (TCR)

• key to cell-mediated immunity 

• T-cells mature in the ‘T’hymus

• Specificity: one T-cell expresses many TCR that recognize the same specific antigen or epitope

• Diversity: every T-cell in the body recognizes a different antigen through their TCR specificity

Helper T-cells (Th cells)

specialized T-cells that express CD4 costimulatory molecule on their cell surface

• Activated when they recognize an antigen-MHC class II complex

• Effector cells: helper T-cells play a key role in the activation of other immune cells

• Memory cells: recognize the same specific antigen, quick and strong response to reinfection of the same pathogen

Cytotoxic T-cells (Tc or CTL)

specialized T-cells that express the CD8 co-stimulatory molecule on their cell surface

• Activated when they recognize an antigen-MHC class I complex

Effector cells: cytotoxic T-cells monitor the cells of the body and eliminate any cells that display a foreign antigen complexed with MHC class I

Memory cells: CD8+ generate memory cells that recognize the same specific antigen

B-cell (B lymphocyte)

non-phagocytic cells that have specific receptors at their cell surface called B-cell receptor (BCR), which are the membrane bound form of antibodies

• Key to humoral immunity

• B cells mature in the ‘B’one marrow

• Specificity: one B-cell expresses many BCR that recognize the same specific antigen (epitope)

• Diversity: every B-cell in the body recognizes a different antigen via BCR specificity

Plasmocytes (plasma cells)

effector form of activated naive B-cells that produce and secrete highly specialized antibodies that can bind free pathogens or foreign molecules in the organism

• Activation of B-cells can also generate memory B-cells that have membrane-bound antibodies (BCR) with the same specificity as the mother cell

Naive

Immunocompetent (mature) cells are considered ‘naive’ until they interact with a foreign antigen for the first time 

Dendritic cells (DC)

phagocyte that can arise from either the myeloid or the lymphoid progenitor cells, part of both innate and adaptive immunity. 

• Function to capture and engulf antigens that evade innate immune response and present them to adaptive immune cells

• DC are the link between innate and adaptive immune systems

Langerhans DC

subtype of DC located under the surface epithelium of the skin and in mucous membranes

Overview of immune cells

History of immunology

• 1796: smallpox vaccine via cross-immunity(Edward Jenner) 

  • Milkmaids that had cowpox were immune to smallpox

• Pasteurization: using heat to destroy pathogens to prevent spoilage (Louis Pasteur)

• Vaccination: attenuated form of a virus leads to immunity (Louis Pasteur) 

• 1890’s: complement system (network of proteins that defend against pathogens) was discovered in 1890 (many scientists)

• 1908: nobel prize

  • Elie Metchnikoff : phagocytic theory that cells can move in order to defend against bacterial infection

  • Paul Ehrlich: humoral immunity, side-chain theory, blood transfusion as treatment

• 1913: Charles Richet nobel prize for discovery of anaphylaxis (hypersensitive reaction)

• 1972: nobel prize Rodney Porter and Gerald Edelman for the structure of antibodies

• 1987: Susumu Tonegawa nobel prize for mechanism of antibody variety generation

• 2011: Jules Hoffman and Bruce Beutler nobel prize for discovery of toll-like receptors

Cross-immunity

form of immunity in which immunity to one bacteria or virus is effective in protecting against an antigenically similar, but different organism

Attenuated

less pathogenic form

Bactericidal

able to kill bacteria

Lipopolysaccharides

large molecules found on the outer membrane of gram-negative bacteria; elicit strong immune responses

What are the 6 major classes of infectious disease-causing agents

1. bacteria

2. viruses

3. fungi

4. protozoa

5. helminths

6. prions

Bacteria

unicellular prokaryotic organisms with no organized internal membranous structures. Genomes are circular double-stranded DNA that do not code for as many proteins as eukaryotic genomes.

Cholera

• Acute diarrheal illness caused by infection of the intestine by bacterium Vibrio Cholerae

• Usually mild, but 1 in 10 has severe disease (profuse diarrhea, vomiting, and leg cramps)

• Contracted by eating or drinking contaminated food

• Diagnosed by stool sample and rectal swab

Viruses

not considered ‘organism’ because it relies on host cell for metabolism and reproduction

• Composed of a viral genome of nucleic acid (DNA or RNA) which can be double or single stranded, that is surrounded by a protein coat (capsid)

• Can also have an outer lipid envelope

Influenza

• Contagious respiratory virus which varies in severity

• Fever, cough, sore throat, runny nose, body aches, headaches

• Spread via droplets of saliva

• Diagnosed by lab tests

Fungi

eukaryotic, heterotrophic organisms that have rigid cellulose or chitin-based cell walls and reproduce by forming spores which cause skin or lung infection

• Divided into molds (multicellular) and yeast (single celled organisms)

Vaginal yeast infection (vulvovaginal candidiasis VVC)

• Overgrowth of the yeast candida in vagina 

• Causes genital itching

• Imbalance of immune system allows candida to multiply

• Visual examination and lab testing of cell sample

• Antifungal cream, ointment, tablets, or suppository

Protozoa

unicellular, heterotrophic eukaryotes without cell walls, allowing for rapid and flexible movements

Malaria

• Mosquito-borne disease caused by a protozoan parasite in the palmodium genus

• Fever, chills, flu-like illness, death

Helminths

parasitic worms; simple invertebrates which are multicellular with differentiated tissues