IMB 401 INTRO TO IMMUNE SYSTEM

Loss of self-tolerance

- Aberrant - Autoimmunity (lupus, type I diabetes)

Defective

- Aberrant - Immune deficiency (SCID, AIDS)

Overreaction

- Aberrant - Hypersensitivity (allergy, asthma)

specificity & diversity

- Adaptive immunity can distinguish between countless different antigens, providing protection against nearly any pathogen an individual may encounter over a lifetime. - This is because each lymphocyte (B or T cell) expresses a unique antigen receptor, and thus collectively, these cells provide incredible diversity of antigen recognition (referred to as the "immune repertoire").

Antibodies

- Also known as immunoglobulins are large Y-shaped plasma proteins that bind to antigens to neutralize/destroy pathogens. - Made by B cells in response to infection or immunization with antigen.

lymph node

- Bean shaped structures, distributed all over the body and linked together by lymphatic vessels - Served by both blood and afferent and efferent lymphatic vessels - Primarily responsible for dealing with infections that arise in tissues.

Thymus

- Bi-lobed organ located above the heart that is the site of T lymphocyte development. It attains maximum size at puberty and becomes smaller, fibrous and fatty with age (weighs about 22 g at birth, 35 g at puberty and 6 g at adult). - Thymic stromal cells secrete several chemokines (chemical messengers) that attract T cell precursors to the thymus.

Spleen

- Bright red organ located below the diaphragm in the upper left quadrant of abdominal cavity (~150-200g in adult) - Filters blood and traps blood-borne antigens - Major site of antibody synthesis - Primarily responsible for coordinating immune response against blood-borne pathogens - Served by blood vessels and drained by efferent lymphatic vessels

Activation molecules

- CD3 - CD28 - CD19 -ECT.

Innate immunity (humoral)

- Complement - Antimicrobial peptides - LPS binding protein - C-reactive protein - Mannose binding lectin

Enzymatic cascade

- Complement system - A chain of inactive enzymes activated by infection, where each cleavage product within the cascade functions to simulate and amplify the inflammatory response.

The alternative pathway

- Continuously active at low levels and spontaneously activates on cells. - Host cells encode inhibitory proteins to prevent this activation but microbes do not.

specialization

- Each immune response is tailored to the type of infection (pathogen) being encountered - The strategy to control an intracellular viral infection must be different from the approach to clearing large extracellular parasites. This information is provided by the innate system as it initially detects the pathogen - different innate receptors can identify whether an invader is a virus, bacteria, parasite, or fungus.

(Immune) memory

- Following the "primary" immune response to the first exposure to a given antigen, a subset of the responding T and B cells are maintained as a "memory" population. - Upon re-exposure to the same antigen, these cells rapidly respond to eliminate the pathogen, providing protection against repeated infections with the same pathogen. - The establishment of immune memory is the goal of vaccination.

Types of adaptive immunity

- Humoral immunity - Cellular immunity

Anatomical & Physiological Barriers

- Intact skin - Ciliary Clearance - Low stomach pH - Lysozyme in tears and saliva

Passive immunization

- Is achieved by the transfer of cells or antibodies from an immunized individual into a non-immunized individual. - Antibodies or sera are usually obtained from humans or animals that have been deliberately immunized or have naturally recovered from active infection.

The classical pathway

- Is initiated by binding of the complement C1qrs protein complex to antibodies (that have already bound their antigen on the surface of a microbe). - This interaction results in a to conformational change in C1qrs, activating the C1s serine protease subunit in the complex.

The lectin pathway

- Is initiated by mannose-binding lectin or ficolin (both complement family proteins) binding directly to the pathogen surface. - These complement proteins recognize carbohydrate motifs on pathogens that aren't present on the host cells. MBL is similarly shaped to the C1qrs complex, and is associated with Mannose-associated serine protease (MASPs). - Upon binding of MBL to the pathogen surface, a conformational change leads to activation of the MASPs. This pathway is antibody independent.

Components of the immune system

- Microbial pathogens are held back by physical (skin) and chemical (lysozyme, low pH) barriers - If barriers are breached, invaders detected first by the innate immune system - Innate immunity contains the initial burst of pathogens (slows them down) and also alerts adaptive immunity to the presence and the type of infection

Innate immunity (cellular)

- Natural killer cells - Eosinophils - Macrophages - Mast cells - Dendritic cells - Neutrophils -Natural killer T cells

Lymphocyte Recirculation & Migration into Tissues

- Naïve lymphocytes constantly recirculate between the blood and peripheral lymphoid organs, monitoring antigen-presenting cells for their specific antigen. - Upon antigen recognition, lymphocytes become activated to become effector cells, which then migrate into tissues to sites of infection to eliminate the pathogen

Immune Rejection

- Normal - Transplant rejection Graft vs Host disease

Fights against infections (cancer)

- Normal - Innate & adaptive immunity, B cell (Ab, humoral) and T cell (cellular response). Vaccines to protect against infections diseases (tumors)

T Cells (Lymphocytes)

- One of the two main cell types of the adaptive immune system (helper T cells, killer T cells and regulatory T cells). - In charge of effecting and regulating the immune response. - Can directly eliminate infectious organisms by stopping their regulation, or killing the cells in which they replicate - Help B cells make antibody and help stop the immune response (regulatory T cells, Treg).

Passive immunization (Natural)

- Protective antibody (IgG) is transferred from mother to infant via the placenta (against diphtheria, tetanus, mumps, rubella). - This provides immunity to the child in the first few months to 1 year of life. IgA transferred from mother to infant via colostrum and breast milk.

Molecules of the immune system

- Recognition molecules - Activation molecules - Trafficking molecules - Elimination/effector molecules

B cells

- Recognize native, unchanged antigen (often 3-dimensional shapes) as pieces (epitopes) of proteins, polysaccharides, nucleic acids, lipids, and happens (small chemicals). - They make and secrete antibodies that can bind that antigen.

T cells

- Recognize only processed (chopped) protein antigens (peptides), bound to self major histocompatibility complex-encoded (MHC) molecules.

Adaptive immunity (cellular)

- T cells - B cells

Types of primary lymphoid organs

- Thymus - Bone marrow

Innate receptors

- Toll-like receptors (TLR) - NOD-like receptors (NLR) - CD4 & CD8 (coreceptors) on T cells

clonal expansion

- When a given (rare) lymphocyte (B or T cell) encounters its antigen during an infection, it undergoes massive clonal expansion, creating identical copies of itself (daughter cells) resulting in an army of identical lymphocytes to patrol the body to seek out and eliminate that antigen (pathogen). - Each cell multiplies to generate up to 1 million copies of itself.

Regions of the spleen

- White pulp - Red pulp

Secondary lymphoid organs

- are the sites where T & B lymphocytes interact with each other and with other cells (e.g. antigen presenting cells = APCs) to mount an immune response against antigens. - There are 450 LN in the human immune system. - There are also Peyer's patches (gut) and other unencapsulated immune tissues (gut, lung, mucosa). - There are ~2x1012 lymphocytes in the body. - Approximately 2% of lymphocytes recirculate each hour, roughly equivalent to the total number of lymphocytes in the blood.

Properties of adaptive immune responses

- specificity & diversity - clonal expansion - memory - specialization - contraction & homeostasis - non-reactivity to self

Secondary (peripheral) lymphoid organs

- spleen - lymph node

Three pathways of complement activation

- the classical pathway - the lectin pathway - the alternative pathway

Antibodies abbreviation

Ab

Elimination/effector molecules

Ab, complement, IFNY, perforin, granzymes

Antigen abbreviation

Ag

Immunogen

An antigen capable of evoking an immune response (e.g. the production of antibodies)

C3 convertase

An enzyme complex of protein subunits that cleaves inactive C3 complement protein into active C3a and C3b fragments

Adaptive immunity (humoral)

Antibodies

Dendrite Cells abbreviation

DC

contraction & homeostasis

Following an immune response, the majority of the antigen-specific cells die by apoptosis, returning the immune system to a balanced state of homeostasis to allow new responses to the next pathogen encountered.

post-splenectomy

Howell-Jolly bodies (nuclear remnants), thrombocytosis, increased susceptibility to encapsulated bacterial infection

Immunoglobulins abbreviation

Ig

Trafficking molecules

Integrins, slectins, adhesins, chemokine receptors, etc. that direct cells to proper site(s) in the body to coordinate the immune response in space

Active immunity

Is induced in an individual by exposure to a foreign antigen via either infection (natural immunity) or deliberate vaccination

Cellular immunity

Is mediated by T cells against both intracellular and extracellular pathogens. There are multiple subclasses of T cells, and each type employs a different defense strategy to combat different class of pathogen.

Humoral immunity

Is mediated by proteins called antibodies, which are produced by B cells, and secreted into the circulation and mucosal fluids to combat extracellular pathogens

spleen dysfunction

Low IgM, low complement activation, increased susceptibility to encapsulated bacterial infection

mannose-binding lectin

MBL

Major histocompatibility complex

MHC

Mucosal immune system

Mucosal responses against microbial pathogens have to be tailored to preserve function of the mucosae (nutrient and gas absorption, secretory, sensory and other roles) and are therefore often less aggressive than those in the skin.

non-reactivity to self

Prevents injury to the host during immune responses to foreign antigens.

Immunity

Protective reaction against foreign particles such as microorganisms or macromolecules. These substances are loosely referred to as antigens (Ag)

Adaptive Immunity

State of immunity developed as a result of exposure to an Ag. Highly specific for each antigen and enhanced by repeated exposure to same Ag.

Cluster of differentiation

System of immune molecule nomenclature

Adaptive Immunity- what type of cells?

T & B cells

Clinical consequences of thymus : congenital

T cell deficiency; removal - early attrition and aging of T cells

Recognition molecules

T cell receptor, B cell receptor; Innate receptors ; MHC class I & II (present antigenic peptides to TCR)

T cell receptor abbreviation

TCR

Innate Immunity

That state of immunity with which one is born. It exists regardless of exposure to antigen and is not enhanced by repeated exposure to antigen

Bone marrow

The Site of B lymphocyte development. It contains hematopoietic stem cells (HSC) which can give rise to all mature cellular elements of the blood (lymphoid, myeloid and erythroid)

Tissues of the immune system

The lymphoid system consists primarily of lymphocytes, accessory cells (dendritic cells, macrophages), epithelia, and connective tissue.

B Cells (Lymphocytes)

The other main cell type of the adaptive immune system. Make antibodies that have numerous and potent anti-infection and regulatory activities

Immune Response

The sum of cellular and molecular events that occur during exposure to foreign, immunogenic substances

Immune System

The sum of molecules, cells and organs that are involved in conferring immunity.

Complement system

a large family of soluble & cell bound proteins that detect pathogen-associated molecular patterns (PAMPs), and immune complexes (antigens bound by antibodies molecules)

Clinical consequences with lymph nodes

any given LN is rarely indispensable as others can compensate, lymphedema

Clinical consequences of bone marrow : damage

aplastic anemia; SCID defect

Primary (central) lymphoid organs

are the sites of lymphocyte development, i.e. where lymphoid stem cells proliferate and differentiate into mature cells (lymphopoiesis). This is the location where lymphocytes acquire antigen receptors and learn to distinguish "self" from "non-self".

Microorganisms

bacteria, fungi, & viruses

Primary organs of the immune system (development)

bone marrow & thymus

Mucosa-associated lymphoid tissue (MALT)

contains 75% of all lymphocytes. Includes gut-associated (GALT), bronchial-associated (BALT) and salivary-associated (SALT) lymphoid tissues.

White pulp

contains B and T lymphocytes which surround arterioles entering the spleen to form the periarteriolar lymphoid sheath (PALS). B cells are located to the outside and the T cells are found inside, allowing them to initiate a compartmentalized immune response and then collaborate with each other

Red pulp

contains RBCs, several types of macrophages, dendritic cells and few lymphocytes and plasma cells. Location where effete red blood cells are destroyed and removed by macrophages. Also, a strategic location for antigen capture from the blood stream

Bone marrow-derived hematopoietic stem cells (HSCs)

give rise to the cellular elements. These include the red blood cells that transport oxygen, platelets which trigger blood clotting in damaged tissues, and cells of the immune system such as lymphocytes, granulocytes, monocytes, natural killer cells

Active Immunization

is induced by exposure to a foreign antigen via either: - Infection (natural immunity) - Deliberate or artificial vaccination with live attenuated organisms (measles), killed organisms ( influenza), inactivated bacterial toxins (tetanus), or microbial components (peptide vaccines)

Adaptive immunity

is slower to develop (days-weeks), but is tailored to be specific for each pathogen, and provides long-term "immunological memory" to respond faster if the same pathogen is encountered later in life. This ability to generate longlived immunologic memory is the basis for vaccination.

Innate immunity

is very fast acting (minutes-hours-days), and provides the immediate, initial protection against infection. Innate cells use pattern-recognition receptors (TLR, NLR, etc.) that recognize common motifs on broad classes of microbes, this ensures broad microbial recognition but is not particularly specific.

Passive immunization (Artificial)

it is NECESSARY in individuals... - Cannot make antibodies (SCID patients) - Immunocompromised individuals who might develop disease before active immunization can stimulate a protective immune responses (usually in 7-10 days). [ex. cancer patients] - Individuals exposed to deadly toxins (black widow spider bite; tetanus toxin). - Adoptive immunization: a form of passive immunization that involves the transfer of cells with the ability to confer immunity. Usually involves transfer to the same (autologous) host (e.g. adoptive transfer of T cells in cancer immunotherapy)

Autoimmunity

may start with an external assault/infection, but the immune system begins responding to self/tissue components.

Macromolecules

proteins, polysaccharides, & nucleic acids

Secondary organs of the immune system (function)

spleen, lymph nodes, Peyer's patches etc.

Hypersensitivity/allergy

the condition in which an antigen that is not actually threatening triggers an inappropriate immune response

Bone marrow

where cells of the immune system originate and where they enter the blood circulation and migrate to tissues

B cell receptor abbreviation

BCR

Cluster of differentiation abbreviation

CD

Passive Immunity

Can be achieved by either natural means [protective antibody (IgG) transferred from mother to infant via placenta] or therapeutic means (transfer of cells or antibodies from an immune individual into an immunologically "naïve" individuals).

Antigen Presenting Cells (APCs)

Cells that capture antigen and present them to T cells. Dendritic cells are the "professional" APC's able to stimulate new immune responses; macrophages and B cells are "nonprofessional" APCs that can support ongoing response