Chapter 6 Diseases of the Immune system: Normal Response Flashcards
1
Q
The Normal Immune Response
A
- INNATE IMMUNITY
- ADAPTIVE IMMUNITY
2
Q
The normal immune response is best understood in the context of defense against infectious
pathogens, the classical definition of immunity.
The mechanisms of protection against infections
fall into two broad categories.
A
- Innate immunity (also called natural, or native, immunity) refers to defense mechanisms that are present even before infection and that have evolved to specifically recognize microbes and protect individuals against infections.
- Adaptive immunity (also called acquired, or specific, immunity) consists of mechanisms that are stimulated by
(“adapt to”) microbes and are capable of recognizing microbial and nonmicrobial substances.
I
3
Q
What are the major components of innate immunity?
A
The major components of innate immunity are:
- epithelial barriers that block entry of microbes,
- phagocytic cells (mainly neutrophils and macrophages),
- dendritic cells,
- natural killer (NK) cells,
- and several plasma proteins, including the proteins of the complement system.
4
Q
What are the two most important cellular reacitons of innate immunity?
A
The two most
important cellular reactions of innate immunity are:
- inflammation, the process in which phagocytic leukocytes are recruited and activated to kill microbes,
- and anti-viral defense, mediated by dendritic cells and NK cells.
5
Q
.What is pathogen associated molecular patterns?
A
Leukocytes and epithelial cells that participate in
innate immunity are capable of recognizing components of microbes that are shared among
related microbes and are often essential for the infectivity of these pathogens (and thus cannot
be mutated to allow the microbes to evade the defense mechanisms). These microbial
structures are called pathogenassociated molecular patterns
6
Q
What is danger associated molecular patterns?
A
Leukocytes also recognize
molecules released by injured and necrotic cells, which are sometimes called dangerassociated
molecular patterns.
7
Q
What are recognition receptors?
A
The cellular receptors that recognize these dangerassociated
molecular patterns molecules are often
called pattern recognition receptors.
8
Q
What is the best defined pattern recognition receptor?
A
The best-defined pattern recognition receptors are a
family of proteins called Toll-like receptors (TLRs) [1] that are homologous to the Drosophila
protein Toll. Different TLRs are specific for components of different bacteria and viruses.
9
Q
Wher are TLRs located?
A
TLRs
are located on the cell surface and in endosomes, so they are able to recognize and initiate
cellular responses to extracellular and ingested microbes.
10
Q
Other microbial sensors are located
in the _______, where they recognize bacteria and viruses that may have colonized cells.
A
cytoplasm
11
Q
What does NF-κB (nuclear factor κB) do?
A
Upon recognition of microbes, the TLRs and other sensors signal by a common pathway that
leads to the activation of transcription factors, notably NF-κB (nuclear factor κB).
NF-κB turns
on the production of cytokines and proteins that stimulate the microbicidal activities of various
cells, notably the phagocytes.
Other cellular receptors bind microbes for phagocytosis; these
include receptors for mannose residues, which are typical of microbial but not host
glycoproteins, and receptors for opsonins such as antibodies and complement proteins that coat microbes.
12
Q
How does the epithelium provide innate immunity?
A
Epithelia of the skin and gastrointestinal and respiratory tracts provide mechanical barriers to
the entry of microbes from the external environment. Epithelial cells also produce anti-microbial
molecules such as defensins, and lymphocytes located in the epithelia combat microbes at
these sites. If microbes do breach epithelial boundaries, other defense mechanisms are called
in.
13
Q
A
Monocytes and neutrophils are phagocytes in the blood that can rapidly be recruited to any site
of infection; monocytes that enter the tissues and mature are called macrophages ( Chapter 2
). Dendritic cells produce type I interferons, anti-viral cytokines that inhibit viral infection and
replication; these cells are described below, in the context of antigen display to lymphocytes.
Natural killer cells provide early protection against many viruses and intracellular bacteria; their
properties and functions are also described below.
14
Q
What are dendritic cells?
A
Dendritic cells produce type I interferons, anti-viral cytokines that inhibit viral infection and
replication; these cells are described below, in the context of antigen display to lymphocytes.
15
Q
How does Natural Killer cells providei innate immunity?
A
Natural killer cells provide early protection against many viruses and intracellular bacteria; their
properties and functions are also described below.
16
Q
How does complement system provide innate immunity?
A
The proteins of the complement system, which were described in Chapter 2 , are some of the
most important plasma proteins of the innate immune system. Recall that in innate immunity the
complement system is activated by microbes using the alternative and lectin pathways; in
adaptive immunity it is activated by antibodies using the classical pathway. Other circulating
proteins of innate immunity are mannose-binding lectin and C-reactive protein, both of which
coat microbes for phagocytosis. Lung surfactant is also a component of innate immunity,
providing protection against inhaled microbes.
17
Q
The early innate immune response not only provides the initial defense against infections but is
also involved in triggering the subsequent, more powerful adaptive immune response.
A
18
Q
The adaptive immune system consists of :
A
The adaptive immune system consists of:
lymphocytes and their products, including antibodies.The receptors of lymphocytes are much more diverse than those of the innate immune system, but lymphocytes are not inherently specific for microbes, and they are capable of recognizing a vast array of foreign substances. In the remainder of this introductory section we focus on
lymphocytes and the reactions of the adaptive immune system
19
Q
What are the two types of adagptive immunity?
A
There are two types of adaptive immunity:
- humoral immunity
- cellular immunity
20
Q
What is humoral immunity?
A
humoral immunity, which protects against
extracellular microbesandtheir toxins,
21
Q
What is cell mediated immunity?
A
cell-mediated (or cellular) immunity,
which is responsible for defense against intracellular microbes
22
Q
Humoral immunity is mediated by ________
A
B (bone marrow–derived) lymphocytes and their secreted products, antibodies (also called
immunoglobulins, Ig),
23
Q
What mediates cellular immunity?
A
cellular immunity is mediated by T (thymus-derived) lymphocytes.
CT
24
Q
What are antigens?
A
Both classes of lymphocytes express highly specific receptors for a wide variety of substances,
called antigens.
25
What are the COMPONENTS OF THE IMMUNE SYSTEM:
COMPONENTS OF THE IMMUNE SYSTEM:
* CELLS,
* TISSUES,
* AND SELECTED MOLECULES
26
Although lymphocytes appear morphologically unimpressive and similar to one another, they
are actually remarkably heterogeneous and specialized in molecular properties and functions.
T or F
True
27
Lymphocytes and other cells involved in immune responses **are not fixed in**
* *particular tissues** (as are cells in most of the organs of the body) but are **capable of migrating**
* *among lymphoid and other tissues and the vascular and lymphatic circulations**
True
28
What are naivee lymphocytes?
In lymphoid organs, different classes of
lymphocytes are anatomically segregated in such a way that they interact with one another only
when stimulated to do so by encounter with antigens and other stimuli. Mature lymphocytes that
have not encountered the antigen for which they are specific are said to be naive (immunologically inexperienced).
29
What are effector cells?
After they are activated by recognition of antigens and other signals described later, lymphocytes differentiate into **effector cell**s, which perform the function
of eliminating microbes, and memory cells, which live in a state of heightened awareness and
are better able to combat the microbe in case it returns. The process of lymphocyte
differentiation into effector and memory cells is summarized below.
30
The principal classes of lymphocytes and their functions in adaptive immunity
* B- lymphocyte: Antibody secretion
* CD4 T helper cells:
* Activation of macrophage
* inflammation
* Stimulation of B lymphocyte
* CD8 Cytotoxic T cell: Killing of infected cell
31
Where do T lymphocytes develop?
T lymphocytes develop from precursors in the **thymus**
**T T**
32
Where can you find mature T cells and it constitute by how much?
1. Mature T cells are found in the **blood**, where they constitute **60% to 70% of lymphocytes,**
2. **an**d in **T-cell zones of peripheral lymphoid organs** (described below)
33
Each T cell recognizes a **specific cell-bound antigen** by means of an
antigen-specific T-cell receptor (TCR)
34
In approximately 95% of T cells the TCR consists of a
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_-
disulfide-linked heterodimer made up of an α and a β polypeptide chain ( Fig. 6-2 ), each
having a **variable (antigen-binding)** region and a constant region
35
The αβ TCR recognizes
peptide antigens that are displayed by \_\_
**major histocompatibility complex (MHC)** molecules on
the surfaces of antigen-presenting cells (APCs).
36
What is MHC restriction?
By **_limiting_ the specificity of T cells for peptides displayed by cell surface MHC molecules,**
called MHC restriction, the immune system ensures that T cells see only cell-associated
antigens (
37
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 chain**s 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.
38
TCR diversity is generated by **\_\_\_\_\_\_\_\_\_\_** of the genes that encode the TCR α and
β chains.
All cells of the body, including lymphocyte progenitors, contain TCR genes in the
germ-line configuration, which cannot be expressed as TCR proteins
**somatic rearrangement**
39
What is RAG-1 and RAG2
During T cell
development in the thymus, the **TCR genes rearrange** to form **many different combinations** that
can be transcribed and translated into functional antigen receptors.
The enzyme in developing
lymphocytes that mediates rearrangement of antigen receptor genes is the **product of RAG-1
and RAG-2**(recombination activating genes)
40
What happens when there is a defect in RAG proteins?
inherited defects in RAG proteins result in a
failure to generate mature lymphocytes.
41
Whereas each T cell expresses TCR molecules of **one specificity,** collectively, **the full complement of T cells** in an individual is **capable of recognizing a**
***_very large number of antigens._***
T or F
True
42
Important : It is important to note that **unrearranged (germ-line) TCR gene**s
are present in **all non-T cells** in the body, **but only T cells contain rearranged TCR genes.**
Furthermore, because each T cell and its clonal
progeny have a unique DNA rearrangement (and hence a unique TCR), it is possible to
distinguish polyclonal (non-neoplastic) T-cell proliferations from monoclonal (neoplastic) T-cell
proliferations. Thus, analysis of antigen receptor gene rearrangements is a valuable assay for
detecting lymphoid tumors
43
Each TCR i**s noncovalently linked to five polypeptide** chains, which form the\_\_\_\_\_\_\_\_\_\_(see Fig. 6-2 ). [4]
CD3 complex and
the ζ chain dimer
The CD3 and ζ proteins are invariant (i.e., identical) in all T cells. They are involved in the transduction of signals into the T cell after the TCR has bound
the antigen. Together with the TCR, these proteins form the “TCR complex.”
44
A small population of mature T cells expresses another type of TCR composed of\_\_\_\_\_\_
polypeptide chains.
γ and δ
45
What does γδ TCR recognizes?
The γδ TCR recognizes p**eptides, lipids, and small molecules, without a
requirement for display by MHC proteins**.
γδ T cells tend to aggregate at epithelial surfaces,
such as the skin and mucosa of the gastrointestinal and urogenital tracts, suggesting that these
cells are **sentinels that protect against microbes that try to enter through epithelia.** However, the
functions of γδ T cells are not known.
46
What are NKT cells?
Another small subset of T cells expresses markers that
are found on NK cells; these cells are called NK-T cells. [6]
NK-T cells express a very limited
diversity of TCRs, and they recognize glycolipids that are **displayed by the MHC-like molecule**
CD1.
The functions of NK-T cells are also not well defined.
47
In addition to CD3 and ζ proteins, T cells express several other proteins that assist the TCR
complex in functional responses. These include
* CD4,
* CD8,
* CD2,
* integrins,
* and CD28
48
\_\_\_\_\_\_\_\_\_\_\_ are expressed on two mutually exclusive subsets of αβ T cells
CD4 and CD8
49
Where is CD4 secreted and what is the function?
CD4 is expressed on approximately **60% of mature CD3+** **T cells,** which function as **cytokine-secreting helper cells
that help macrophages and B lymphocytes to combat**infections
50
Where is CD8 expressed and what is the function?
CD8 is expressed on
about 30% of T cells, which function as **cytotoxic (killer) T lymphocytes (CTLs)** to **destroy host
cells harboring microbes**
51
Why is CD4 and CD8 are co receptors?
CD4 and CD8 serve as “coreceptors” in T-cell activation, so called because **they work with the antigen recepto**r in responses to antigen.
```
During antigen
presentation, **CD4 molecules bind to class II MHC** molecules that are displaying antigen (see
Fig. 6-2 ), and **CD8 molecules bind to class I MHC** molecules.
```
When the antigen receptor of a T
cell recognizes antigen, the **CD4 or CD8 coreceptor initiates signals that are necessary for
activation of the T cells.** Because of this requirement for co-receptors, CD4+ helper T cells can
recognize and respond to antigen displayed only by class II MHC molecules, whereas CD8+
cytotoxic T cells recognize cell-bound antigens only in association with class I MHC molecules;
this segregation is described below.
52
During antigen presentation, CD4 binds to where?
During antigen
presentation, CD4 molecules bind to **class II MHC** molecules that are displaying antigen (see
Fig. 6-2 )
4-2
53
Where does CD8 binds during antigen presentation?
CD8 molecules bind to class **I MHC molecules**
Batch 81
54
To respond, T cells have to recognize **not only antigen-MHC complexes** **but additional signals
provided by APCs.** We will describe these later, when we summarize the steps in cell-mediated
immune responses
55
B lymphocytes develop from precursors in the \_\_\_\_\_\_\_\_\_\_\_\_\_-
bone marrow.
56
Mature B cells constitute \_\_\_\_\_\_\_\_\_- of the circulating peripheral lymphocyte population and are **also present in peripheral
lymphoid tissues such as lymph nodes, spleen, and mucosa-associated lymphoid tissues**
10% to 20%
T cell \> B cell
T for tantamount
57
How do B cells recognize antigen?
**B-cell antigen receptor complex.**
58
What is the component of the B-cell receptor complex?
Membrane-bound antibodies
called **IgM and IgD**, present on the surface of all mature, naive B cells, are the antigen-binding
component of the B-cell receptor complex
59
Do B cell receptors have the same unique antigen specificity as with T cell?
Yes
As with T cells, each B-cell receptor has a
unique antigen specificity, **derived from RAG-mediated rearrangements of Ig genes**.
Thus, as in
T cells, analysis of Ig gene rearrangements is useful for **identifying monoclonal B-cell tumors .**
60
After stimulation by antigen and other signals (described later), B cells what happens to B cells?
develop into **plasma**
**cells** that **secrete antibodies,** the **mediators of humoral** **immunity**.
In addition to membrane Ig, the
**B-cell antigen receptor complex contains a heterodimer** of two invariant proteins called **Igα and** **Igβ.**
Similar to the CD3 and ζ proteins of the TCR complex, **Igα and Igβ are essential for signal**
transduction through the **antigen receptor**.
61
B cells also express several other molecules that are
essential for their responses.
These include :
* complement receptors,
* Fc receptors,
* and CD40.
The **type 2 complement receptor (CR2, or CD21**) is also the receptor for the Epstein-Barr virus
**(EBV), and hence EBV readily infects B cells**
TWO - ONE ( CD21 ) poot is infected with EBV
62
FIGURE 6-3 Structure of antibodies and the B-cell antigen receptor.
A, The B-cell receptor complex is composed of:
* **membrane immunoglobulin M (IgM; or IgD,** not shown), which recognize 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. (
63
There are **two types of cells** with **dendritic morphology** that are **functionally quite different**.
Both
have numerous fine cytoplasmic **processes that resemble dendrites**, from which they derive
their name.
1. interdigitating dendritic cells, or just dendritic cells
2. follicular dendritic cell .
64
Whati are nterdigitating dendritic cells, or just dendritic cells?
These cells are the **most important antigen-presenting cells (APCs)** for **initiating primary T-cell**
responses against protein antigens (described later)
65
Several features of dendritic cells account
for their key role in antigen presentation.
* First, these cells are **located at the right place** **to** **capture antigens**—under epithelia, the common site of entry of microbes and foreign antigens, and in the interstitia of all tissues, where antigens may be produced. Immature dendritic cellswithin the epidermis are called **Langerhans cells.**
* Second, dendritic cells **express many** **receptors** for capturing and responding to microbes (and other antigens), including TLRs and mannose receptors.
* Third, in response to microbes, dendritic cells are **recruited to the T-cell** **zones of lymphoid organs,** where they are ideally located to present antigens to T cells.
* Fourth, dendritic cells **express high levels of the molecules** needed for presenting antigens to and activating CD4+ T cells.
66
What are Langerhan's cells?
Immature dendritic cells
within the epidermis are called Langerhans cells.
67
Describe the other type of dendritic cell which is the **follicular dendritic cell?**
The other type of cell with dendritic morphology is **present in the germinal centers of lymphoid**
**follicles in the spleen and lymph node**s and is hence called **follicular dendritic cel**l . [9]
These
cells **bear Fc receptors for IgG** and **receptors for C3b** and **can trap antigen bound to antibodies**
or complement proteins.
Such cells play a role in humoral immune responses by **presenting antigens to B cells** and **selecting the B** cells that have the highest affinity for the antigen, thus
improving the quality of the antibody produced.
68
What are the important functions in the induction and effector phases of adaptive immune responses of MACROPHAGES?
• Macrophages that have phagocytosed microbes and protein antigens **process the antigens** and present peptide fragments to T cells.
Thus, macrophages **function as APCs** in **T-cell** activation.
• Macrophages are **key effector cells** in certain forms of cell-mediated immunity, the reaction that serves to eliminate intracellular microbes.
In this type of response, **T cells
activate macrophages and enhance their ability to kill ingested microbes** (discussed
below).
• Macrophages also **participate in the effector phase** of **humoral immunity.** As discussed in
Chapter 2 , macrophages efficiently phagocytose and destroy microbes that are
opsonized (coated) by IgG or C3b.
69
NK cells make up approximately how many percent in the peripheral blood lymphocyte?
10% to 15% of peripheral blood lymphocytes.
70
natural killer cells **do not
express TCRs or Ig.**
## Footnote
**T or F**
T
71
What is the morphology of NK cells?
Morphologically, NK cells are somewhat **larger than small lymphocytes,** and
they **contain abundant azurophilic granules;** because of these characteristics, they are also
called **large granular lymphocytes.**
72
Why are NK cells also called **large granular lymphocytes?**
Morphologically, NK cells are somewhat larger than small lymphocytes, and
they contain abundant azurophilic granules; because of these characteristics, they are also
called large granular lymphocytes.
73
What are the capabilities of NK cells?
NK cells are endowed with the **ability to kill a variety of
infected and tumor cells, *_without*_ _*prior exposure_* to or activation by these microbes or tumors.**
This ability makes NK cells **an early line of defense against viral infections and, perhaps, some
tumors.**
74
What are the two cell surface molecule commonly used to id NK cells?
Ywo cell surface molecules, **CD1_6_ and CD5**_6_****, are commonly used to i**dentify NK cells**
**Killer is number 6 for Devils**
75
What is **antibody-dependent cell-mediated cytotoxicity (ADCC)?**
* *CD16 is an Fc receptor for IgG**, and it confers on NK cells the **ability to lyse IgG-coated target**
cells. This phenomenon is known as **antibody-dependent cell-mediated cytotoxicity (ADCC)**
76
The functional activity of NK cells is r**egulated** by a **balance between signals** from **activating
and inhibitory receptors**
* activating receptors
* **NKG2D family**
* inhibitory receptors recognize self–class I MHC molecules
* killer cell Ig-like receptors
* and the **CD94 family of lectins (carbohydrate-recognizing proteins).**
77
The NKG2D receptors recognize surface molecules
that are induced by \_\_\_\_\_\_\_\_
various kinds of stress, such as infection and DNA damage.
78
NK cell
inhibitory receptors recognize \_\_\_\_\_\_\_\_\_\_\_
**self–class I MHC molecules,** which are _expressed on all healthy_ _cells_
79
```
NK cell inhibitory receptors recognize self–class I MHC molecules, which are expressed on all healthy
cells.
```
These receptors belong to **two major families:**
The inhibitory receptors prevent NK cells
from killing normal cells. Virus infection or neoplastic transformation often induces expression of
ligands for activating receptors and at the same time reduces the expression of class I MHC
molecules. As a result the balance is tilted toward activation, and the infected or tumor cell is
killed.
* killer cell Ig-like receptors
* and the **CD94family of lectins (carbohydrate-recognizing proteins).**
80
FIGURE 6-5 Activating and inhibitory receptors of natural killer (NK) cells.
```
A, **Healthy cells** **express self–class I MHC molecules,** which are recognized by inhibitory receptors, thus
ensuring that NK cells do not attack normal cells.
```
Note that healthy cells may express ligands
for activating receptors (not shown) or may not express such ligands (as shown), but they do not activate NK cells because they engage the inhibitory receptors.
```
B, In i**nfected and** **stressed cells, class I MHC** expression is reduced so that the inhibitory receptors are not engaged, and ligands for activating receptors are expressed. The result is that NK cells are
activated and the infected cells are killed
```
81
NK cells also secrete cytokines, such as :
* **interferon-γ (IFN-γ**), which activates macrophages todestroy ingested microbes, and thus NK cells provide early defense against intracellular microbial infections.
* The activity of NK cells is regulated by many cytokines, including the interleukins **IL-2, IL-15, and IL-12. IL-2 and IL-15** stimulate proliferation of NK cells, whereas **IL-12 activates killing and secretion of IFN-γ.**
82
What does interferon-γ (IFN-γ) does?
interferon-γ (IFN-γ), which **activates macrophages** to
**destroy ingested microbes**, and thus **NK cells provide early defense against intracellular
microbial infections.**
83
What are the cytokines that regulate NK cells?
The activity of NK cells is **regulated** by many cytokines, including the interleukins:
* **IL-2,**
* **IL-15,**
* **IL-12.**
Feb 15 2012 after valentines day : Regulate fertility!
84
What stimulates the proliferation of NK cells?
**IL-2 and IL-15** stimulate proliferation of NK cells
Feb 15 is POST VALENTINES **STIMULATION**
85
What activates killing and secretion of IFN-y?
**IL-12 activates killing and secretion of IFN-γ.**
**2012** sabi end of the world eto killing time!
86
Tissues of the Immune System
* Generative Lymphoid Organs
* Peripheral Lymphoid Organs
* Lymphocyte Recirculation
87
The principal generative lymphoid organs are the :
* **thymu**s, where T cells develop,
* **bone** **marrow**, the site of production of all blood cells and where B lymphocytes mature.
88
The peripheral lymphoid organs consist of the :
* **lymph nodes,**
* **spleen,**
* and the **mucosal and** **cutaneous lymphoid tissues.**
**** These tissues are organized to concentrate antigens, APCs, and lymphocytes in a way that optimizes interactions among these cells and the development of
adaptive immune responses.
89
Describe lymphnodes.
Lymph nodes are **nodular aggregates** of lymphoid tissues **located along lymphatic channels**
throughout the body ( Fig. 6-6 ).
As lymph passes through lymph nodes, APCs in the nodes are able to sample the antigens of microbes that may enter through epithelia into tissues and are
carried in the lymph.
In addition, dendritic cells pick up and transport antigens of microbes from epithelia via the lymphatic vessels to the lymph nodes.
Thus, the antigens of microbes that
enter through epithelia or colonize tissues become concentrated in draining lymph nodes.
90
FIGURE 6-6 Morphology of a lymph node
* A, The histology of a lymph node, with an outer cortex containing follicles and an inner medulla.
* B, The segregation of B cells and T cells in different regions of the lymph node, illustrated schematically.
* C, The location of B cells (stained green, using the immunofluorescence technique) and T cells (stained red) in a lymph node.
91
Describe the spleen.
The spleen is an **abdominal organ** that serves the same role in immune responses to bloodborne
antigen as that of lymph nodes in responses to lymph-borne antigens.
Blood entering the
spleen flows through a network of **sinusoids**.
**Blood-borne antigens are trapped by dendritic
cells and macrophages in the spleen.**
92
The cutaneous and mucosal lymphoid systems are located :
* **epithelia of the skin** and
* the **gastrointestinal and respiratory tracts,** respectively. They respond to antigens that enter by breaches in the epithelium.
93
What are the two anatomically defined mucosal lymphoid tissues?
* Pharyngeal tonsils
* Peyer's patches of the intestine
94
At any time, more than half the body's
lymphocytes are in the mucosal tissues (reflecting the large size of these tissues), and many of
these are memory cells
95
```
Within the peripheral lymphoid organs, T lymphocytes and B lymphocytes are segregated into
different regions (see Fig. 6-6 ).
```
* **B cells**-----**follicles**
* **T lymphocytes--- paracortex**
**BF: B**eefy **f**ries
**TP: T**a**Pa**
96
What is a foliicle?
In lymph nodes the **B cells are concentrated in discrete
structures**, called follicles,
97
What are **germinal centers?**
If the B cells in
a follicle have **recently responded to an antigen**, this follicle may contain a **central region called
a germinal center .**
98
What is a paracortex?
The **T lymphocytes are concentrated** in the paracortex, **adjacent to the**
**follicles.**
The follicles contain the follicular dendritic cells that are involved in the activation of B
cells, and the paracortex contains the dendritic cells that present antigens to T lymphocytes. In
the spleen, T lymphocytes are concentrated in periarteriolar lymphoid sheaths surrounding
small arterioles, and B cells reside in the follicles.
99
The follicles contain the
**follicular dendritic cells** that are involved in the activation of B cells,
100
paracortex contains:
paracortex contains the **dendritic cells that present antigens to T lymphocytes**.
101
In the spleen, where is T lymphocytes concentrated :
in **periarteriolar lymphoid sheaths** surrounding
small arterioles, and **B cells reside in the follicles.**
102
The anatomic organization of peripheral lymphoid organs is t**ightly regulated to allow immune**
**responses to develop**. [11] [12] [13]
The location of B cells and T cells in the lymphoid follicles and paracortical areas, respectively, is **dictated by chemokines** produced in these anatomic
locales.
When the lymphocytes are activated by antigens they alter their expression of chemokine receptors.
As a result, the B cells and T cells leave their homes, migrate toward
each other and meet at the edge of follicles, where helper T cells interact with and help B cells
to differentiate into antibody-producing cells.
103
Lymphocytes constantly recirculate between tissues and home to particular sites.
T or F
T
104
naive
lymphocytes traverse the peripheral lymphoid organs where\_\_\_\_\_\_\_\_\_\_\_\_-
**effector lymphocytes** migrate to :\_\_\_\_\_\_\_\_\_\_\_\_
**immune responses are initiated,**
**sites of infection and inflammation**
105
This
process of lymphocyte recirculation is most relevant for\_\_\_\_\_\_\_\_\_\_\_\_\_
T cells, because effector T cells have to
locate and eliminate microbes at any site of infection.
By contrast, plasma cells remain in
**lymphoid organs** and **do not need to migrate to sites of infection because they secrete
antibodies** that are carried to distant tissues. Therefore, we will limit our discussion of
lymphocyte recirculation to T lymphocytes.
" kaya nga nasa foliicle area sila unlike T cells located at the parafollicular.
106
FIGURE 6-7 Migration of naive and effector T lymphocytes.
Naive T lymphocytes home to
lymph nodes as a **result of L-selectin** and **integrin** binding to their ligands on **high endothelial
venules (HEVs)**.
Chemokines expressed in lymph nodes **(called CCL19 and CCL21)** bind to **receptors (CCR7) on naive T cells,** enhancing integrin-dependent adhesion and inducing
migration of the cells through the HEV wall.
Activated T lymphocytes, including effector and
memory cells, home to sites of infection in peripheral tissues, and this migration is mediated
by **E-selectin and P-selectin, integrins, and chemokines secreted at inflammatory sites** (e.g.,
CXCL10) that are recognized by chemokine receptors (e.g., CXCR3) that are expressed on
activated T cells.
**APC, antigen-presenting cell; ICAM-1, intercellular adhesion molecule 1;
VCAM-1, vascular cell adhesion molecule 1.**
107
What are HEVs?
Naive T lymphocytes that have exited the thymus **migrate to lymph nodes** and **enter the T-cell**
**zones** through **specialized postcapillary venules**, called **high endothelial venules (HEV**s) (see
Fig. 6-7 )
**HEV** is an aiplane from thymus to migrate to lymph nodes
. In the lymph node, a naive T cell may encounter the antigen that it specifically
recognizes on the surface of an APC and is activated. During this process, the cells alter their
expression of adhesion molecules and chemokine receptors. Differentiated effector T cells
ultimately leave the lymph nodes, enter the circulation, and migrate into the tissues that harbor
the microbes
108
What is the major Histocompatibility Complex (MHC) Molecules?
Peptide Display System of Adaptive Immunity
109
What is the physiologic funciton of MHC?
The physiologic function of MHC
molecules is to **display peptide fragments of protein**s for **recognition by antigen-specific T
cells.**
**" Presentor/ Displayer"**
110
In humans the genes encoding MHC is on?
In humans the genes encoding the major histocompatibility molecules are clustered
on a small segment of **chromosome 6**, the major histocompatibility complex , **or the human
leukocyte antigen (HLA) complex**( Fig. 6-8 ), so named because in**humans MHC-encoded
proteins were initially detected on leukocytes by the binding of antibodies**
111
Why is it that in humans MHC is also called as HLA?
so named because in humans MHC-encoded
proteins were **initially detected on leukocytes by the binding of antibodies**
112
HLA system is highly polymorphic?
T or F
T
The HLA system is
**highly polymorphic**, meaning that there are many alleles of each MHC gene in the population
and each individual inherits one set of these alleles that is different from the alleles in most
other individuals. This, as we see subsequently, constitutes a formidable barrier in organ
transplantation.
113
FIGURE 6-8 The human leukocyte antigen (HLA) complex and the structure of HLA
molecules
* . A, The location of genes in the HLA complex. The relative locations, sizes, and distances between genes are not to scale. Genes that encode several proteins involved in antigen processing (the TAP transporter, components of the proteasome, and HLA-DM) are located in the class II region (not shown).
* B, Schematic diagrams and crystal structures of
class I and class II HLA molecules.
114
On the basis of their structure, cellular distribution, and function, MHC gene products are
classified into three groups.
* **Class I MHC** molecules are **expressed on all nucleated cells and platelets**
* **Class II MHC** molecules are encoded in a region called **HLA-D**, which has three
subregions: HLA-DP, HLA-DQ, and HLA-DR
* The **MHC locus also contains genes that encode some complement components** and
the **cytokines tumor necrosis factor (TNF**) and lymphotoxin, as well as some proteins
that have no apparent role in the immune system.
115
Describe Class I MHC.
Class I MHC molecules are **expressed on all nucleated cells and platelets.**
They are
encoded by three closely linked loci, designated **HLA-A, HLA-B, and HLA-C**
116
Each class I MHC molecule is a heterodimer consisting of a :
polymorphic α, or heavy, chain (44-kD) linked noncovalently to a smaller (12-kD) nonpolymorphic peptide called **β2-microglobulin**, which is not encoded within the MHC.
The extracellular region of the α
chain is divided into three domains: **α1, α2, and α3.** Crystal structure of class I
molecules has revealed that the α1 and α2 domains form a cleft, or groove, where
peptides bind. [16]
The polymorphic residues line the sides and the base of the peptidebinding
groove; the variation in this region explains why different class I alleles bind
different peptides.
117
FIGURE 6-9 Antigen processing and display by major histocompatibility complex (MHC)
molecules.
* A, In the class I MHC pathway, peptides are produced from proteins in the cytosol and transported to the endoplasmic reticulum (ER), where they bind to class I MHC molecules. The peptide-MHC complexes are transported to the cell surface and displayed for recognition by CD8+ T cells.
* B, In the class II MHC pathway, proteins are ingested into vesicles and degraded into peptides, which bind to class II MHC molecules being transported in the same vesicles. The class II–peptide complexes are expressed on the cell surface and recognized by CD4+ T cells.
118
Class I MHC molecules display peptides that are derived from :
Class I MHC molecules display peptides that are derived from:
* proteins, such as viral antigens, that are located in the cytoplasm and usually produced in the cell.
119
```
class I–associated
peptides are recognized by\_\_\_\_\_\_\_\_
```
CD8+ T lymphocytes
120
```
What is class I
MHC–restricted?
```
```
CD8+ T cells recognize peptides only if
presented as a complex with self–class I MHC molecules, CD8+ T cells are said to be class I
MHC–restricted
```
121
Cytoplasmic proteins are degraded in proteasomes and peptides are transported into the endoplasmic reticulum (ER) where the peptides bind to newly synthesized class I molecules. [17]
Peptide-loaded MHC
molecules associate with β2-microglobulin to form a stable trimer that is transported to the cell surface.
The nonpolymorphic α3 domain of class I MHC molecules has a binding site for CD8, and therefore the peptide–class I complexes are recognized by CD8+ T cells, which function as CTLs.
In this interaction, the TCR recognizes the MHC-peptide complex, and the CD8 molecule,
acting as a coreceptor, binds to the class I heavy chain. Thus, CD8+ cytotoxic T cells recognize
peptides that are produced by cytoplasmic microbes (typically viruses) or in tumors and kill cells
harboring these infections or the tumor cells. Since CD8+ T cells recognize peptides only if
presented as a complex with self–class I MHC molecules, CD8+ T cells are said to be class I
MHC–restricted. Because one of the important functions of CD8+ CTLs is to eliminate viruses,
which may infect any nucleated cell, it makes good sense that all nucleated cells express class I
HLA molecules and can be surveyed by CD8+ T cells.
122
Class II MHC molecules are encoded in a region called \_\_\_\_\_\_\_\_\_
Class II MHC molecules are encoded in a region called **HLA-D**, which has three subregions: **HLA-DP, HLA-DQ,** and HLA-DR.
123
Describe the class II molecule.
```
Each class II molecule is a heterodimer
consisting of a noncovalently associated α chain and β chain, both of which are polymorphic.
```
The extracellular portions of the α and β chains have two domains each: **α1, α2 and β1, β2**.
```
Crystal structure of class II molecules has revealed that, **similar to** **class I molecules**, they have peptide-binding clefts facing outward [16] (see Fig. 6-8 ).
This cleft is formed by an interaction of the α1 and β1 domains, and it is in this portion that most class II alleles differ.
```
Thus, as with class I molecules, polymorphism of class II molecules is associated with differential binding of antigenic peptides.
124
Class II MHC molecules present antigens that are \_\_\_\_\_\_\_\_\_\_
internalized into vesicles, and are typically
derived from extracellular microbes and soluble proteins
125
Describe the Class II MHC molecules present antigens that are **internalized into vesicles**, and are typically
derived from extracellular microbes and soluble proteins ( Fig. 6-9B ).
The internalized proteins
are **proteolytically digested** in endosomes or lysosomes.
Peptides **resulting from proteolytic**
* *cleavage** then **associate with class II heterodimers** in the vesicles, and the **stable peptide-MHC**
* *complexes are transported to the cell surface**.
The **class II β2 domain** has a binding site for
* *CD4**, and therefore, the **class II–peptide complex is recognized by CD4+ T cells,** which function
* *as helper cells.**
In this interaction, the **CD4 molecule acts as the co-receptor**.
```
Because CD4+ T
cells **can recognize antigens only in the context of self–class II molecules**, they are referred to
as **class II MHC–restricted**.
```
126
In contrast to class I molecules, class II MHC molecules are:
mainly expressed on cells that **present ingested antigens** and **respond to T-cell help (macrophages, B**
**lymphocytes, and dendritic cells).**
127
```
The **class II β2 domain** has a binding site for
\_\_\_\_\_\_\_\_\_,
```
CD4
```
and therefore, the class II–peptide complex is recognized by **CD4+ T** cells, which function
as **helper cells**
```
**Class 2: CD4**
Age **24 Im very helpful!!!!**
128
Explain **class II MHC–restricted.**
In this interaction, the CD4 molecule acts as the co-receptor. Because CD4+ T
cells can recognize antigens only in the context of self–class II molecules, they are referred to
as **class II MHC–restricted.** In contrast to class I molecules, class II MHC molecules are mainly
expressed on cells that present ingested antigens and respond to T-cell help (macrophages, B
lymphocytes, and dendritic cells).
129
WHat is an MHC locus?
The MHC locus also contains genes that encode some complement components and
the cytokines tumor necrosis factor (TNF) and lymphotoxin, as well as some proteins
that have no apparent role in the immune system.
```
The class II locus contains genes that
encode many proteins involved in antigen processing and presentation, such as
components of the proteasome, peptide transporter, and a **class II–like molecule called
DM**that facilitates peptide binding to class II molecules.
```
130
Describe HLA haplotype..
The **combination of HLA alleles in each individua**l is called the HLA haplotype.
Any given
individual i**nherits one set of HLA genes** from each parent and thus **typically expresses two
different molecules**for every locus.
Because of the **polymorphism of the HLA loci,** virtually
innumerable combinations of molecules exist in the population, and **each individual expresses
an MHC profile on his or her cell surface that is different from the haplotypes of most other
individuals**.
It is believed that this polymorphism evolved to ensure that at least some individuals
in a species would be able to display any microbial peptide and thus provide protection against
any infection.
The same polymorphism means that **no two individuals** (other than identical twins)
are **likely to express the same MHC molecules,** and therefore grafts exchanged between these
individuals are recognized as foreign and attacked by the immune system.
131
MHC molecules play key roles in regulating T cell–mediated immune responses in several
ways
* First, because different antigenic peptides bind to different MHC molecules, it follows that an individual mounts an immune response against a protein antigen only if he or she inherits the gene(s) for those MHC molecule(s) that can bind peptides derived from the antigen and present it to T cells. The consequences of inheriting a given MHC (e.g., class II) gene depend on the nature of the antigen bound by the class II molecule. For example, if the antigen is a peptide from ragweed pollen, the individual who expresses class II molecules capable of binding the antigen would be genetically prone to allergic reactions against pollen. In contrast, an inherited capacity to bind a bacterial peptide may provide resistance to the infection by evoking a protective antibody response.
* Second, by segregating cytoplasmic and internalized antigens, MHC molecules ensure that the correct immune response is mounted against different microbes —CTLs against cytoplasmic microbes, and antibodies and macrophages (both of which are activated by helper T cells) against extracellular microbes.
132
HLA and Disease Association
The diseases
that show association with the HLA locus can be broadly grouped into the following categories:
* **1. Inflammatory diseases** including ankylosing spondylitis and several postinfectious
arthropathies, all associated with HLA-B27
* **2. Autoimmune diseases**, including autoimmune endocrinopathies, associated mainly with
**alleles at the DR locus**
* 3. Inherited errors of metabolism, such as 21-hydroxylase deficiency (HLA-BW47) and
hereditary hemochromatosis (HLA-A)
1.
133
Association of HLA Alleles and Inflammatory Diseases
HLA Allele
B27
1. Ankylosing spondylitis
2. Postgonococcal arthritis
3. Acute anterior uveitis
134
Association of HLA Alleles and Inflammatory Diseases
**HLA Allele**
**DR4**
1. Rheumatoid arthritis
2. Type 1 diabetes
135
Association of HLA Alleles and Inflammatory Diseases
HLA Allele
DR3
* Chronic active hepatiti
* Primary Sjögren syndrome
* Type 1 diabetes
136
In the immunological
and inflammatory diseases, the inheritance of particular HLA alleles **likely influences** the \_\_\_\_\_, but it has proved difficult to define precisely how.
In some cases (e.g., 21-
hydroxylase deficiency), the linkage results because the r**elevant disease-associated gene**, in
this case the gene for 21-hydroxylase, maps within the **HLA complex.**
Similarly, in hereditary
hemochromatosis, a gene that is mutated, called HFE, maps within the HLA locus. The HFE
protein resembles MHC molecules structurally, but its function is in the regulation of iron
transport
T-cell
response,
137
What are cytokines?
The induction and regulation of immune responses involve multiple interactions among
lymphocytes, dendritic cells, macrophages, other inflammatory cells (e.g., neutrophils), and
endothelial cells.
Some of these interactions depend on cell-to-cell contact; however, many
interactions and effector functions of leukocytes are mediated by short-acting secreted
mediators called **cytokines**.
138
What are interleukins?
Molecularly defined cytokines are called **interleukins,** because they mediate communications between leukocytes.
Most cytokines have a wide spectrum of effects,
and some are produced by several different cell types.
139
It is convenient to classify cytokines into distinct functional classes, although many belong to
multiple categories.
* Cytokines of innate immunity
* Cytokines of adaptive immune responses
* colony-stimulating factors
140
Cytokines of innate immunity are produced rapidly in response to microbes and other
stimuli, are made principally by macrophages, dendritic cells, and NK cells, and mediate
inflammation and anti-viral defense;
these include:
* TNF,
* IL-1,
* IL-12,
* type I IFNs,
* IFN-γ,
* and chemokines
141
Cytokines of adaptive immune responses are made principally by **CD4+ T lymphocytes**
in response to antigen and other signals, and function to promote lymphocyte
proliferation and differentiation and to activate effector cells.
The main ones in this
group are: their roles in immune responses are
described below.
* IL-2,
* IL-4,
* IL-5,
* IL-17,
* and IFN-γ
142
What colony-stimulating factors?
Some cytokines stimulate hematopoiesis and are called **colony-stimulating factors**
because they are assayed by their ability to stimulate formation of blood cell colonies
from bone marrow progenitors ( Chapter 13 ). Their functions are to increase leukocyte
numbers during immune and inflammatory responses, and to replace leukocytes that
are consumed during such responses.
143
The knowledge gained about cytokines has numerous practical therapeutic applications.
Inhibiting cytokine production or actions is an approach for controlling the harmful effects of
inflammation and tissue-damaging immune reactions. Patients with rheumatoid arthritis often
show dramatic responses to TNF antagonists, an elegant example of rationally designed and
molecularly targeted therapy. Conversely, recombinant cytokines can be administered to
enhance immunity against cancer or microbial infections (immunotherapy).
144
