Chapter 6 - Diseases of the Immune System Flashcards Preview

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Flashcards in Chapter 6 - Diseases of the Immune System Deck (126)
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1

Two broad categories of immunity

Innate immunity (a.k.a. natural, native immunity): mechanisms ready to react to infections before they occur.  These have evolved to recognize and combat microbes.  First line of defense

 

Adaptive immunity (a.k.a. acquired, specific immunity): Mechanisms that are stimulated by microbes and are capable of recognizing microbial and nonmicrobial substances. Develops later than, and is stronger than innate immunity.

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The principal mechanisms of innate immunity and adaptive immunity. NK cells, Natural killer cells.

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Innate immunity functions in three stages

1. Recognition of microbes

2. Activation of various mechanisms

3. Elimination of unwated substances

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What are the major components of innate immunity?

1. Epithelial barriers (i.e. skin, GI, respiratory tract) - provide mechanical barriers to microbial entry from external environment.  Epithelial cells also produce antimicrobial molecules (i.e. defensins)

2. Phagocytic cells (monocytes, macrophages, neutrophils) - sense the presence of, and ingest harmful microbes

3. Dendritic cells (interstitial, plasmacytoid, langerhans)- Specialized cells in epithelia, lymphoid organs, most tissues, that capture protein antigens and display them for T-lymphs to recognize.  They also secrete cytokines, mediating inflammation. Key in innate immunity, not part of adaptive immunity.

4. Natural killer cells - Provide early protection against viruses and intracellular bacteria

5. Several other cell types (mast cells, others) can sense and react to microbes

6. Innate lymphoid cells - Recently discovered cells that lack TCRs, but produce cytokines similar to T cells

7. Soluble proteins (complement proteins, mannose-binding lectin, C-reactive protein)- activated by microbes using alternative and lectin pathways in innate responses; activated by antibodies in classical pathway in adaptive responses.  MBL and CRP coat microbes, promoting phagocytosis of them.  Lung surfactant is also part of innate immunity against inhaled microbes

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Cells that participate in innate immunity are capable of recognizing certain microbial components that are shared among related microbes and are often essential for infectivity (and thus cannot be mutated to allow the microbes to evade the defense mechanisms). 

What are these microbial structures called?

 

What are the receptors that recognize these molecules called?

Pathogen-associated molecular patterns (PAMPs)

Leukocytes also recognize molecules released by injured/necrotic cells Damage-assocaited molecular patterns (DAMPs)

 

Receptors are called pattern recognition receptors (PRRs)

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Pattern recognition receptors are located in all the cellular compartments where microbes may be present: plasma membrane receptors detect extracellular microbes, endosomal receptors detect ingested microbes, and cytosolic receptors detect microbes in the cytoplasm

 

What are some categories of PRRs?

1. Toll-like receptors (TLRs)

2. NOD-like receptors (NLRs) and the inflammasome

3. C-type lectin receptors (CLRs)

4. RIG-like receptors (RLRs)

5. Mannos receptors

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Toll-like receptors

Ten different TLRs in mammalian cells, each recognizing a different set of microbial molecules. 

They may be present in plasma membranes or endosomal vesicles.

They all signal via a common pathway that culminates in in the activation of 2 sets of transcription factors:
(1) NF-kB - stimulates synthesis and secretion of cytokines and expression of adhesion molecules
(2) interferon regulatory factors (IRFs) - stimulates production of antiviral cytokines (type I interferons)

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NOD-like receptors and the Inflammasome

NLRs are cytosolic receptors. that recognize a wide variety of substances (i.e. uric acid, ATP, ion disturbances, some microbial products)

Inflammasome: cytosolic multiprotein complex which activates caspase-1 that cleaves and activates IL-1 

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The inflammasome. The inflammasome is a protein complex that recognizes products of dead cells and some microbes and induces the secretion of biologically active interleukin 1. The inflammasome consists of a sensor protein (a leucine-rich protein called NLRP3), an adapter, and the enzyme caspase-1, which is converted from an inactive to an active form.

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C-type lectin receptors (CLRs)

Expressed on plasma membranes of macrophages and dendritic cells, and detect fungal glycans, eliciting an inflammatory response to fungi

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RIG-like receptors (RLRs)

Cytosolic receptors in most cell types; detect nucleic acids of viruses that replicate in teh cytoplasm of infected cells.

These stimulate production of antiviral cytokines.

G protein-coupled receptors on leukocytes recognize N-formylmethionyl residues on bacterial organisms, stimulating chemotactic responses in these cells.

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Mannose receptors

Recognize microbial surgars (they have terminal mannose residues, unlike mammalian glycoproteins), and induce phagocytosis of microbes)

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Cellular receptors for microbes and products of cell injury. Phagocytes, dendritic cells, and many types of epithelial cells express different classes of receptors that sense the presence of microbes and dead cells. Toll-like receptors (TLRs) located in different cellular compartments, as well as other cytoplasmic and plasma membrane receptors, recognize products of different classes of microbes. The four major classes of innate immune receptors are TLRs, NOD-like receptors in the cytosol (NLRs), C-type lectin receptors (CLRs), and RIG-like receptors for viral nucleic acids (RLRs).

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The innate immune systeme provides host defense by 2 main reactions:

1. Inflammation: Cytokines complement fragments, other mediators, are produced during innate immune reactions and trigger vascular and cellular components of inflammation.  

2. Antiviral defense: Type I interferons produced in response to viruses act on infected and uninfected cells and activate enzymes that degrade viral nucleic acids and inhibit their replication - antiviral state

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A few major differences between innate and adaptive immunity

1. Innate immunity does not have memory or fine antigen specificity, like adaptive immunity has.

2. Innate immunity uses about 100 receptros to recognize 1,000 molecular patterns, while adaptive immunity uses two receptor types (antibodies and TCRs), each with millions of variations 

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What are the two types of adaptive immunity?

There are two types of adaptive immunity: humoral immunity, which protects against extracellular microbes and their toxins, and cell-mediated immunity, which is responsible for defense against intracellular microbes.

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Are lymphocytes and other cells involved in immune responses fixed in particular tissues?

No

 

They constantly circulate among lymphoid and other tissues via blood and lymphatic circulation

This provides immune surveillance

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What are naive, effector, and memory lymphocytes?

1. Naive lymphocytes - mature lymphocytes that have not yet encountered antigen for which they are specific

2. Effector cells - Lymphocytes that have recognized antigen, become activated, and differentiated in order to eliminate microbes

3. Memory cells - Lymphocytes that have recognized antigen, become activated, and differentiated in order to live in a state of heightened awareness and can react strongly and rapidly to combat the microbe if it returns

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The principal classes of lymphocytes and their functions. B and T lymphocytes are cells of adaptive immunity and natural killer (NK) cells are cells of innate immunity. Several more classes of lymphocytes have been identified, including NK-T cells and so-called innate lymphoid cells (ILCs); the functions of these cells are not established.

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What is the fundamental concept of clonal selection?

Lymphocytes specific for a large number of antigens exist before exposure to antigen, and when an antigen enters, it selectively activates the antigen-specific cells.

Clones - Lymphocytes of the same specificity that express identical antigen receptors.  

With 1012 lymphocytes that are capable of recognizing 107-109 different antigens, there are very low numbers of cells specific for any one antigen

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What generates antigen receptor diversity?

Antigen receptor diversity is generated by somatic recombination of genes that encode the receptor proteins.

Recombination activating genes (RAG-1, RAG-2) produce enzymes in developing lymphocytes that mediate gene recombination.  

All cells in the body contain the germline antigen receptor genes, but only T and B cells contain recombined gnees (TCR, Ig)

 

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Each T or B cell and its clonal progeny have a unique DNA rearrangement (and a unique antigen receptor).  What is the clinical significance of this?

It is possible to distinguish polyclonal (nonneoplastic) from monoclonal (neoplastic) lymphoid proliferations.  Analysis of antigen receptor gene rearrangement is a valuable assay for detecting tumors derived from lymphocytes.

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What are the three major populations of T lymphocytes?

1. Helper T lymphocytes stimulate B lymphocytes to make antibodies and activate other leukocytes to destroy microbes.

2. Cytotoxic T lymphocytes kill infected cells

3. Regulatory T lymphocytes limit immune responses and prevent reactions against self-antigens.

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Where do T cells mature and where are mature ones located?

T cells develop in the thymus from precursors that arise from hematopoietic stem cells.

Mature T cells are in the blood, where they constitute 60-70% of lymphocytes, and are in T-cell zones of peripheral lymphoid organs.

 

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T cell receptor (TCR) structure and function

TCR consists of a heterodimer made up of an alpha and a beta polypeptide chain, each with a variable antigen binding and a constant region.

Each TCR is linked to an invariant CD3/zeta protein complex (6 polypeptide chains), w hich is involved in signal transduction

TCR + this complex = TCR complex

The ab-TCR recognizes peptide antigens that are presented by major histocompatibility complex (MHC) molecules on the surfaces of antigen-presenting cells.

 

A small population of mature T cells have a gamma-delta (yd) TCR which recognizes peptides, lipids, and small molecules WITHOUT the need for MHC proteins.  These aggregate at epithelial surfaces (GI, resp, urogen, skin), which may indicate they are sentinels, but their functions are unknown

 

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The T-cell receptor (TCR) complex and other molecules involved in T-cell activation. The TCR heterodimer, consisting of an α and a β chain, recognizes antigen (in the form of peptide-MHC complexes expressed on antigen-presenting cells, or APCs), and the linked CD3 complex and ζ chains initiate activating signals. CD4 and CD28 are also involved in T-cell activation. (Note that some T cells express CD8 and not CD4; these molecules serve analogous roles.) The sizes of the molecules are not drawn to scale. MHC, Major histocompatibility complex.

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In addition to CD3 and zeta proteins, T cells express several other proteins that assist the TCR complex in functional responses.  What are some of these?

1. CD4 - coreceptor for T helper cells that binds to MHC II molecules (expressed on professional APCs) (~ 60% of mature T cells)

2. CD8 - coreceptor for cytotoxic t cells that binds to MHC I molecules (~30% of mature T cells)

3. CD28 - Recognize signals from antigen-presenting cells

4. Integrins - cell-cell and cell-matrix adhesion

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What is the only cell in the body capable of producing antibodys and ar mediators of humoral immunity?

B-cells!

They develop from precursors in the marrow; mature B-cells comprise 10-20% of circulating peripheral lymphocyte population and are present in peripheral lymphoid tissues (LNs, spleen, MALT)

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How do B-cells recognize antigen?

Through the B-cell antigen receptor complex

Membrane-bound antibodies (IgM and IgD) are on all mature, naive B cells and are the antigen-binding component of the B-cell receptor  complex

B-cell antigen receptor complex also contains a heterodimer of two invariant proteins (Ig-alpha (CD79a), and Ig-beta (CD79b)), which are essential for signal transduction.

B-cells also express:
(1) Type 2 complement receptor (CR2, or CD21) which recognizes complement products generated during innate immunity (CR2 is also used by Epstein-Barr virus as a receptor to enter/infect B cells)
(2) CD40 - receives signals from helper T cells

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Structure of antibodies and the B-cell antigen receptor. A, The B-cell antigen receptor complex is composed of membrane immunoglobulin M (IgM; or IgD, not shown), which recognizes antigens, and the associated signaling proteins Igα and Igβ. CD21 is a receptor for a complement component that also promotes B-cell activation. B, Crystal structure of a secreted IgG molecule, showing the arrangement of the variable (V) and constant (C) regions of the heavy (H) and light (L) chains.