BIO 444 EXAM1

lymphoid cells

Three main types of cells develop from the common lymphoid progenitor •B lymphocytes •T lymphocytes •Natural killer cells (NK cells) Lymphocytes appear very similar, but different sets carry different proteins - clusters of differentiation (CD) molecules - on their surface

Antigen Presenting Cells (APC)

To activate T cells, their receptors must recognize protein fragments presented by antigen presenting cells (APCs): •the immune system has a highly specialized system for capturing and displaying antigens to lymphocytes •dendritic cells, monocytes, macrophages and B cells can all act as antigen-presenting cells

Toll-Like Receptors (TLR)

Toll-like receptors (TLRs) recognize many types of pathogen molecules: •Homologous to fruit fly Toll receptor

B & T Lymphocytes (B & T Cells)

Two main types - B-cells and T-cells: •B-cells develop into plasma cells •Plasma cells make antibodies •T-cells attack viruses, cancer cells Cell surface receptors: •Each B or T cell expresses a single type •Effector B cells (plasma cells) secrete soluble immunoglobulins (antibodies) •T cell receptors are only ever expressed as cell surface receptors

Pathogens fall into four major categories

Viruses Bacteria Fungi Parasites

MHC class I

accommodates peptides 8 - 9 amino acids long •are expressed on all nucleated cells •Found throughout the body •present peptides to CD8+ T cells •presents intracellular antigen peptides •show which cells have been infected with viruses or are abnormal

Lymphatic vessels begin

as open-ended capillaries:•feed into larger and larger lymphatic vessels•empty into the bloodstream by a series of ducts

Spleen

attached to the lateral border of the stomach•first line of defense against bloodborne pathogens•red blood cells are compartmentalized in red pulp•white blood cells are segregated in white pulp

Hematopoiesis

blood cell formation •In adults, occurs in the bone marrow of skull, ribs, sternum, vertebral columns, pelvis & femurs

Hematopoietic stem cells (HSCs)

cells (HSCs) can differentiate into many types of blood cells: •All red (erythrocytes) and white (leukocytes) blood cells develop from a pluripotent HSC during hematopoiesis

Lymphoid nodules

found in the located in the respiratory and digestive tracts :•simple structures•dense cluster of lymphocytes without a surrounding fibrous capsule•tonsils are lymphoid nodules located along the inner surface of the pharynx •important in developing immunity to oral pathogens

Two types of adaptive immunity

humoral and cell mediated

basophils

inflammation/allergies •accumulate at sites of infection •large nucleus, obscured by granules •large, dark blue-purple granules •rare and poorly understood •involved in immune responses to parasites - granules are released in presence of IgE

Lymphoid Cells

lymphocytes, macrophages, dendritic cells, reticular cells

Phagocytes include

macrophages and neutrophils

•lymphoid progenitor cells

most of are the mediators of adaptive immune responses

Granulocytes

neutrophils, eosinophils, basophils •Have irregular-shaped nuclei with 2-5 lobes •Have prominent cytoplasmic granules •Contain reactive molecules that kill microbes

MHC class II

peptide ends are free and the peptide length is variable •are expressed mainly on dendritic cells, macrophages, and B lymphocytes •present peptides to CD4+ T cells •presents extracellular antigen peptides •Helps to direct responses against threats―things that shouldn't be in our systems

Pattern recognition receptors (PRRs)

recognize these structures and target them for clearance

•myeloid (nonlymphoid) cells

red blood cells (erythrocytes) megakaryocyte (platelets) monocytes granulocytes

Cytokine

signaling molecule cells use to communicate with each other over short distances: •Injured cells, phagocytes, and basophils secrete inflammatory mediators, including prostaglandins and leukotrienes •Leukotrienes attract neutrophils from the blood by chemotaxis and increase vascular permeability •Prostaglandins cause vasodilation by relaxing vascular smooth muscle and are a major cause of the pain associated with inflammation. • Nonsteroidal anti-inflammatory drugs such as aspirin and ibuprofen relieve pain by inhibiting prostaglandin production

Epithelial barriers are major components of innate immunity that include

skin gastrointestinal tract respiratory tract

Chemokines

soluble chemical mediator that attracts cells (chemotaxis) from longer distances.

lymphedema

swelling due to an abnormal accumulation of lymph fluid within the tissues

Cluster of differentiation (CD):

-Markers important in immunity -Found on the membranes of a variety of different cells involved in the immune response -Over 300 have been described

Three types of blood cells

1.Erythrocytes (red blood cells) 2.Leukocytes (white blood cells) 3.Platelets (thrombocytes)

The two most important cellular reactions of innate immunityThe two most important cellular reactions of innate immunity

1.Inflammation the process in which phagocytic leukocytes are recruited and activated to kill microbes 2.Antiviral defense mediated by dendritic cells and NK cells

Eosinophils

1.antiviral activity, antiparasite activity •leave blood system after a few hours, enter respiratory and GI tracts •phagocytose antigen-antibody complexes •produce histaminase - high eosinophil blood count may indicate an allergic reaction •bi-lobed nucleus (rarely 3 lobes) •numerous medium-sized orange-red granules

The principal components of innate immunity are:

1.physical and chemical barriers epithelia and antimicrobial chemicals produced at epithelial surfaces 2.innate lymphoid cells phagocytic cells (neutrophils, macrophages), dendritic cells, and natural killer (NK) cells 3.blood proteins members of the complement system and other mediators of inflammation

Primary lymphoid organs:Organs where B cells & T cells mature

1.the bone marrow 2.thymus gland

Neutrophils

A type of white blood cell that engulfs invading microbes and contributes to the nonspecific defenses of the body against disease. •live for < a day - self destruct after one burst of activity •forms pus at site of infection •circulate in blood for 6-10 hours, then enter tissues

Monocytes

An agranular leukocyte that is able to migrate into tissues and transform into a macrophage.

Antigens

An antigen is any molecule that stimulates an immune response: •Most antigens are proteins or polysaccharides

The Exogenous Pathway of Antigen Processing and Presentation (MHC2)

Antigens destined for the class II MHC pathway are internalized from the extracellular environment: •APCs ingest extracellular microbes or microbial proteins •microbial proteins enter acidic intracellular vesicles (phagosome/endosome), which fuse with lysosomes •proteins are broken down by proteolytic enzymes, generating many peptides of varying lengths

White Blood Cells (WBCs or Leukocytes

Attack pathogens •all WBCs can move like amoeba, migrating out of blood vessels into surrounding tissues •much less common than red blood cells 5000-10,000 WBCs per microliter of blood •Nucleated cells Five types: Neutrophils Lymphocytes Monocytes Eosinophils Basophils

lymph nodes

Bean-shaped filters that cluster along the lymphatic vessels of the body. They function as a cleanser of lymph as wells as a site of T and B cell activation

Extravasation

the passage of cells through the intact vessel wall: •cell adhesion molecules mediate neutrophil adhesion to the endothelium •leukocytes extend pseudopodia and pass through gaps between endothelial cells •once in the interstitial fluid, leukocytes migrate along a chemotactic gradient towards the site of injury or infection

The Endogenous Pathway of Antigen Processing and Presentation (MHC1)

Cytosolic antigens are processed for display by Class I MHC: •peptides are transported from the cytosol to the rough endoplasmic reticulum •MHC class I molecules are synthesized on ribosomes in the rough endoplasmic reticulum

Dendritic cells are the most important APC

Dendritic cells (DCs) are most efficient at taking up antigens and processing them for presentation to T cells: •DC are present at all epithelial barriers & ingest invading pathogens •Upon this stimulus, DC migrate to local lymph nodes, where they present pathogen antigens to T cells •This initiates specific immunity DC are critical for crosstalk between innate and adaptive immunity

Pattern Recognition Receptors (PRR) are expressed on phagocytes & other leukocytes:

Families of PRRs recognize a wide variety of PAMP ligands: •Toll-like receptors (TLRs) •C-type lectin receptor (CLR) •RIG-I-like receptor (RLR) •NOD-like receptors (NLRs) Signaling pathways are activated, contributing to innate/inflammatory responses

Major Histocompatibility Complex (MHC)

Histocompatibility Complex (MHC): •MHC molecules are membrane glycoproteins •display peptide antigens on APCs for recognition by T lymphocytes •two different classes: MHC class I MHC class II •Also known as human leukocyte antigens (HLAs) •~10,000 MHC molecules on the surface of an APC

Mucosa-associated lymphoid tissue (MALT):

Important layer of defense against infection at mucosal and epithelial layers•Organizes responses to antigens that enter mucosal tissues•Includes a network of follicles and lymphoid microenvironments associated with the intestines (gut-associated lymphoid tissue, or GALT)•e.g. Peyer's patches (B cell follicle) in the small intestin

Damage-Associated Molecular Patterns (DAMPs)

Innate immune system also recognizes molecular patterns of damaged or necrotic tissue: •Response eliminates aging, dead or damaged cells •Initiates tissue repair •Repair occurs following internal injuries e.g. blood vessel blockages

Immune response is initiated in secondary lymphoid organs :

Lymph nodes SpleenMucosa-associated lymphoid tissue (MALT)•All connected via the blood and lymphatic systems•Areas where immune cells encounter antigens, become activated, undergo clonal expansion, and differentiate into effector cells

the lymphatic system

Lymphatic system is a system of vessels, cells, ducts, and organs:•carries excess fluids to the bloodstream and filters pathogens •blood pressure causes leakage of fluid from the capillaries•fluid accumulates in the interstitial space - interstitial fluid

T lymphocytes (T cells)

Lymphocyte that matures in the thymus and acts directly against antigens in cell-mediated immune responses.

Structure of MHC Molecules

MHC class I and II both contain an extracellular peptide-binding cleft: •MHC class 1 cleft can accommodate peptides typically 8 to 9 amino acids long MHC class II form a cleft large enough to accommodate 10 to 30 amino acidresidues

Erythrocytes

Most common blood cell •Small, anucleate (no nucleus), biconcave cells •7 μm in diameter •Contain hemogloblin protein that binds oxygen has red pigment, heme •Approx 4.5 - 5 million RBCs per microliter blood Essential for transport of oxygen & carbon dioxide

Natural Killer (NK) Cells

NK cells are a type of lymphocyte that can induce apoptosis (programmed cell death):

How do cells recognize foreign material

PAMPs - pathogen associated molecular patterns: •leukocytes and epithelial cells that participate in innate immunity recognize components of microbes that are shared among related microbes •often essential for survival or infectivity of pathogen •microbe cannot evade by mutation

Platelets (Thrombocytes)

Platelets: •Small, 2-4 µm diameter •No nucleus, but have mitochondria •Fragments from large cells called megakaryocytes •Form plugs to stop bleeding •Secrete chemicals that aid clotting clotting prevents blood loss many clotting factors in plasma clotting factors released by injured tissue & platelets clotting factors initiate clotting - formation of fibrin from soluble fibrinogen

Capture of Protein Antigens by Antigen-Presenting Cells

Protein antigens of microbes are captured by dendritic cells and concentrated in the secondary lymphoid organs: •upon activation, DC lose their adhesiveness for epithelia •CD begin to express the chemokine receptor CCR7, which is specific for cytokines produced by lymphatic endothelium and by cells in the T cell zones of lymph nodes •DC migrate to the lymph nodes

Antigen Processing

Proteins in the cytosol of any nucleated cell are processed in proteolytic complexes called proteasomes and displayed by class I MHC molecules: •proteasomes - proteolytic complexes •proteasome is made of stacked rings of proteolytic enzymes •degrade proteins into peptide fragments •extracellular proteins internalized by specialized APCs are processed in endosomes and lysosomes and displayed by class II MHC molecules

Recognition Molecules of the Innate Immune System

Receptors of the innate immune system are varied: •Recognize features shared by pathogens •Not specific for a particular pathogen •Major PAMPs are: nucleic acids, including DNA, dsRNA, ssRNA, surface glycoproteins (GP) lipoproteins (LP) bacteria/fungal membrane components peptidoglycans [PG] & GPI anchors

lukocytes

white blood cells

How do lymphocytes locate and react rapidly to antigen?

• → Antigen presentation - cells present protein fragments to T lymphocytes (T cells)

In normal blood there are

•5 - 10 x 106 red cells per microliter •1 - 5 x 103 white cells per microliter •1.5 - 4 x 105 platelets per microliter

Inflammation

•Accumulation and activation of leukocytes and plasma proteins at the site of infection or tissue injury •Proinflammatory cytokines and chemokines triggered by innate responses to infection, damage, or harmful substances •Early components of inflammation include: •Increased vascular permeability •Recruitment of neutrophils and other leukocytes from the blood to the site of damage/infection

Epithelial layers produce protective substances

•Acidic pH •Enzymes and binding proteins lysozyme in mucosal/glandular secretions •Antimicrobials defensins (disrupt membranes) fatty acids & lactic acid secretions

Cytokines (soluble proteins) induce local dilation of blood capillaries:

•Causes skin to warm & turn red •Vasodilation introduces gaps between endothelial cells that line blood vessels •Plasma leaks, causing edema & swelling •Leukocytes are recruited

MHC locus encodes three major classes of molecules:

•Class I MHC genes •Class II MHC genes •Class III MHC genes Complement and inflammation proteins

Mast cells

•Found in all connective tissue •Have granules like basophiles, but dissimilar & progenitor cell is unknown •Activation & degranulation of mast cells contribute to inflammation

There are 3 main types of T cells

•Killer T cells (cytotoxic T cells or CTLs) kill virally infected cells and tumors •Helper T cells (TH) help other cells of the immune system •Regulatory T cells (Treg)

Dendritic cells

•Live in tissues, have a star-shaped morphology •Similar function to macrophages, also act as cellular messengers to call up adaptive immune response •Take up pathogens & deliver them to lymphoid tissues

MHC genes are highly polymorphic

•MHC molecules are among the most polymorphic of all proteins in mammals •many different alleles (variants) are present in the population. •>14,000 alleles ~ 10,500 class I and 3500 class II molecules •up to 6 class I and about 12 class II molecules expressed per person •prevents pathogens from avoiding presentation by mutation

Humoral and cell-mediated immunity relies on surface receptors (B- and T-cell receptors):

•These are randomly generated by gene segment rearrangements in B and T cells •B cells that encounter antigen produce the antibody specificity of their cell membrane immunoglobulin •T-cell receptors bind specific peptides presented by MHC molecules

Cytotoxic

•activated NK cells kill cells infected with intracellular pathogens, such as obligate intracellular bacteria and viruses, and tumors

MHC genes are co-dominantly expressed:

•alleles inherited from both parents are expressed equally •maximizes the number of HLA proteins expressed by each individual •enables individuals to display a large number of peptides •genes in an MHC haplotype are tightly linked and inherited together •chance that two siblings will inherit identical sets of HLA alleles is 25%

Innate immunity

•also called natural immunity or native immunity •provides immediate protection against microbial invasion

Adaptive immunity

•also called specific immunity or acquired immunity •requires proliferation and differentiation of lymphocytes in response to microbes

Neutrophils are granulocytes

•attracted via chemotaxis from the bloodstream to infected tissues •granulocyte contains cytoplasmic granules •granules contain a variety of vasoactive mediators, such as histamine

Humoral immunity

•combats pathogens via antibodies Antibodies are produced by B cells Antibodies can be transferred between individuals to provide passive immunity

Cell-mediated immunity

•involves primarily T cells These can eradicate pathogens, clear infected self-cells, or aid other cells in inducing immunity

Macrophages

•move through tissues and squeeze through capillary walls using pseudopodia •participate in innate immune responses and cooperate with lymphocytes in the adaptive immune response •macrophages freely roam through connective tissues or fixed to reticular fibers within specific tissues, such as lymph nodes •called different names, depending on the tissue: Kupffer cells in the liver histiocytes in connective tissue alveolar macrophages in the lungs

Hematopoietic stem cells differentiate into two major types of progenitor cells:

•myeloid (nonlymphoid) cells •lymphoid progenitor cells

A phagocyte is a cell that can surround and engulf a particle or cell, a process called phagocytosis

•phagocytes engulf particles or cells •clean up debris or to kill pathogenic organisms •phagocytes are the body's fast acting, first line of immunological defense against organisms that have breached barrier defenses and have entered the body

Lymphocytes

•second most common, 20-25% WBCs •small, 6-9 μm in diameter •large nucleus, stains dark purple •no visible granules •light blue cytoplasm

How do lymphocytes locate and react rapidly to antigen

•very few naive lymphocytes are specific for any one antigen •~1 in 105 or 106 circulating lymphocytes •it is impossible for lymphocytes of all possible specificities to efficiently patrol all these sites searching for foreign invaders