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Recognition of foreignness
➢ Distinguishing between self and nonself is essential in maintaining host integrity.
This distinction is highly specific and selective so as to eliminate invading
pathogens but not destroy host tissue.
➢ The modern use of tissue transplantation, where organs, tissues, and cells from
unrelated persons are carefully matched to the self-recognition markers on the
recipient’s cells when used in disease treatment.
The Major Histocompatibility Complex (MHC)
➢ (MHC) is a collection of genes on chromosome 6 in humans and chromosome 17
in mice. The MHC is also called the human leukocyte antigen (HLA) complex in
humans and the H-2 complex in mice.
➢ Almost all human cells contain HLA molecules on their plasma membranes.
➢ HLA molecules can be divided into three classes: class I molecules are found on all
types of nucleated body cells; class II molecules appear only on cells that can process
nonself materials and present antigens to other cells (i.e., macrophages, dendritic cells,
and B cells);
➢ Class III molecules include various secreted proteins that have immune functions.
Unlike class I and II MHC molecules, class III molecules are mostly secreted products
whose presence is not required to discriminate between self and nonself.
➢ Furthermore, the class III MHC molecules are not membrane proteins, are not related to
class I or II molecules, and have no role in antigen presentation.
➢ Each individual has two sets of MHC genes—one from each parent, and both are
expressed (i.e., they are codominant). Thus a person expresses many different HLA
products.
The MHC region of human chromosome 6 and the gene products
associated with each locus
➢ The HLA proteins differ among individuals; the closer two people are related,
the more similar are their HLA molecules.
➢ In addition, many forms of each HLA gene exist. This is because multiple
alleles of each gene have arisen by high gene mutation rates, gene
recombination, and other mechanisms (i.e., each gene locus is polymorphic).
➢ The differences in the HLA products expressed by individuals appear to
account for some of the variation in infectious disease susceptibility.
➢ Class I molecules comprise HLA types A, B, and C and serve to identify
almost all cells of the body as “self.”
➢ They also stimulate antibody production when introduced from one host into
another host with different class I molecules. This is the basis for MHC typing
when a patient is being prepared for an organ transplant.
➢ Class II HLA molecules are produced only by certain white blood cells, such as
activated macrophages, dendritic cells, mature B cells, some T cells, and certain
cells of other tissues.
➢ Class II molecules are required for T-cell communication with macrophages,
dendritic cells, and B cells.
➢ Part of the T-cell receptor must recognize a peptide within a class II molecule on
the antigen-presenting cell before the T cell can secrete cytokines necessary for
the immune response.
Class I MHC molecules
➢ MHC1 are transmembrane glycoproteins consist of a complex of two protein chains,
one with a mass of 45,000 Daltons (Da), known as the alpha chain, and the other
with a mass of 12,000 Da (β2-microglobulin).
➢ The alpha chain can be divided into three functional domains, designated α1, α2, and
α3. The α3 domain is attached to the plasma membrane by a short amino acid
sequence that extends into the cell interior, while the rest of the protein protrudes to
the outside.
➢ The β2-microglobulin (β2m) protein and α3 segment of the alpha chain are
noncovalently associated with one another and are close to the plasma membrane.
➢ The α1 and α2 domains lie to the outside and form the antigen-binding pocket.
Class II MHC molecules
➢ MHC11 are also transmembrane glycoproteins consisting of α and β chains of
mass 34,000 Da and 28,000 Da, respectively.
➢ Both chains combine to form a three dimensional protein pocket, the antigen-
binding pocket, into which a nonself peptide fragment can be captured for
presentation to other cells of the immune system.
➢ Although MHC class I and class II molecules are structurally distinct, both fold
into similar shapes.
➢ Each MHC molecule has a deep groove into which a short peptide derived from
a foreign substance can bind. Because this peptide is not part of the MHC
molecule, it can vary from one MHC molecule to the next.
Structure of MHC1 & MHC11 Proteins
The space-filling model of a class I MHC protein holding shorter peptide antigens (blue) than
does a class II MHC. (d)
➢ Foreign peptides in the MHC groove must be present to activate T cells, which in turn
activate other immunocytes.
➢ By binding and presenting foreign peptides, class I and class II molecules inform the
immune system of the presence of nonself.
➢ These peptides arise in different places within cells as the result of a process known as
antigen processing.
➢ Class I molecules bind to peptides that originate in the cytoplasm. Foreign peptides
within the cytoplasm of mammalian cells come from replicating viruses or other
intracellular pathogens, or the result of cancerous transformation.
➢ These intracellular antigenic proteins are digested by a cytoplasmic structure called the
proteasome, as part of the natural process by which a cell continually renews its protein
contents.
➢ The resulting short peptide fragments are pumped by specific transport proteins
from the cytoplasm into the endoplasmic reticulum.
➢ Within the endoplasmic reticulum the class I MHC alpha chain is synthesized
and associates with β2 microglobulin. This dimer appears to bind antigen as
soon as the foreign peptide enters the endoplasmic reticulum.
➢ The class I MHC molecule and antigenic peptide are then carried to, and
anchored in, the plasma membrane. In this way, the host cell presents the
antigen to a subset of T cells called CD8, or cytotoxic, T lymphocytes.
➢ CD8 T cells bear a receptor that is specific for class I MHC molecules that
present antigen, these T cells bind and ultimately kill infected host cells.
➢ Class II MHC molecules bind to fragments that initially come from antigens
outside the cell.
➢ This pathway functions with bacteria, viruses, and toxins that have been taken up
by endocytosis.
➢ APC, such as a macrophage, dendritic cell, or B cell, takes in the antigen or
pathogen by receptor mediated endocytosis or phagocytosis, and produces
antigen fragments by digestion in the phagolysosome.
➢ Fragments then combine with preformed class II MHC molecules and are
delivered to the cell surface.
Antigen-processing
pathways. (MHC
Class I and Class II)
Antigen Processing
and Presentation
➢ It is here that the peptide is recognized by CD4 T-helper cells.
➢ Unlike CD8 T cells, CD4 T cells do not directly kill target cells. Instead they
respond in two distinct ways.
➢ One is to proliferate, thereby increasing the number of CD4 cells that can react
to the antigen.
➢ Some of these cells will become memory T cells, which can respond to
subsequent exposures to the same antigen.
➢ The second response is to secrete cytokines (e.g., interleukin- 2) that either
directly inhibit the pathogen that produced the antigen or recruit and stimulate
other cells to join in the immune response.
Physical barriers in nonspecific (innate)
resistance
➢ Many direct factors (nutrition, physiology,
fever, age, genetics) and equally as many
indirect factors (personal hygiene,
socioeconomic status, living conditions)
influence all host-microbe relationships.
➢ Physical and Mechanical Barriers
➢ Skin outer layer consists of thick, closely
packed cells called keratinocytes, which
produce keratins. Keratins are scleroproteins
(i.e., insoluble proteins) that make up the main
components of hair, nails, and the outer skin
cells.
➢ These outer skin cells shed continuously,
removing any grime or microorganisms that
manage to adhere to their surface.
▪ The skin is slightly acidic (around pH 5 to
6) due to skin oil, secretions from sweat
glands, and organic acids produced by
commensal staphylococci.
▪ skin-associated lymphoid tissue (SALT).
One type of SALT cell is the Langerhans
cell, a specialized myeloid cell that can
phagocytose antigens.
▪ The epidermis also contains another type of
SALT cell called the intraepidermal
lymphocyte.
Mucous Membranes
▪ The mucous membranes of the eye (conjunctiva) and the respiratory, digestive, and
urogenital systems withstand microbial invasion.
▪ Mucus contain lysozyme, an enzyme that lyses bacteria by hydrolyzing the
bacterial cell wall peptidoglycan.
▪ Mucus contain IGA antibody
▪ They also contain significant amounts of the iron-binding protein, lactoferrin.
Lactoferrin is released by activated macrophages and polymorphonuclear leukocytes
(PMNs).
▪ Lactoferrin sequesters iron from the plasma, reducing the amount of iron available
to invading microbial pathogens and limiting their ability to multiply.
▪ Mucous membranes produce lactoperoxidase, an enzyme that catalyzes the production
of superoxide radicals, a reactive oxygen intermediate that is toxic to many
microorganisms
▪ mucus-associated lymphoid tissue (MALT). There are several types of MALT e.g
GALT, BALT
▪ The mucociliary apparatus for removal of bacteria in the respiratory tract is aided by
the pulmonary macrophages. Special protective mechanisms in the respiratory tract
include the hairs at the nares and the cough reflex, which prevents aspiration.
▪ In the gastrointestinal tract, several systems function to inactivate bacteria: Saliva
contains numerous hydrolytic enzymes; the acidity of the stomach kills many ingested
bacteria (eg, Vibrio cholerae), and the small intestine contains many proteolytic
enzymes and active macrophages. Both factors can destroy microorganisms in the
small intestine.
▪ Most mucous membranes of the body carry a constant normal microbiota that
itself opposes establishment of pathogenic microorganisms (“bacterial
interference”).
▪ For example, in the adult vagina, an acidic pH is maintained by normal
lactobacilli, inhibiting establishment of yeasts, anaerobes, and gram-negative
bacteria.
Complement System
▪ The complement system includes serum and membrane bound proteins that function
in both innate and adaptive host defense systems.
▪ The complement system proteins are synthesized by the liver, and circulate in the
blood as inactive precursors.
▪ Several complement components are proenzymes, which must be cleaved to form
active enzymes. The components are numbered from C1 to C9, and the reaction
sequence is C1-C4-C2-C3-C5-C6-C7-C8-C9.
▪ Biologic Effects of Complement System
▪ Activation of complement results in four major outcomes: (1) cytolysis, (2)
chemotaxis, (3) opsonization, and (4) anaphylatoxins.
▪ Cytolysis is the lysis of cells, such as bacteria, virus infected cells, and tumor cells. This
process occurs through the development of the membrane attack complex (MAC) (C5b,
6, 7, 8, 9), which inserts into the membrane of an organism or cell. The MAC leads to
loss of osmotic integrity and cell lysis.
▪ Chemotaxis is a process in which an immune cell, usually a phagocyte, is attracted to
and moves toward a soluble factor. For example, C5a is a potent chemotactic agent that
stimulates movement of neutrophils and monocytes toward sites of antigen deposition.
▪ Opsonization is a process in which microorganisms and antigen–antibody complexes
become coated with molecules that bind to receptors on phagocytes. Phagocytosis is
more efficient in the presence of C3b because of the presence of C3b receptors on
phagocytes.
▪ Anaphylatoxins promote vasodilation and increased vascular permeability. Both C3a
and C5a are potent promoters of vasodilation and vascular permeability.
▪ These two complement components also stimulate mast cells and basophils to release
histamine. This function of complement results in an increased blood flow to the site
of infection, allowing more complement, antibodies, and immune cells to enter the site
of infection.
Fever
▪ Fever is the most common systemic manifestation of the inflammatory response and is a
cardinal symptom of infectious disease. The ultimate regulator of body temperature is the
thermoregulatory center in the hypothalamus.
▪ Among the substances capable of inducing fever (pyrogens) are endotoxins of gram-
negative bacteria and cytokines released from lymphoid cells, such as IL-1.
▪ Various activators can act upon mononuclear phagocytes and other cells and induce them
to release IL-1. Among these activators are microbes and their products; toxins, including
endotoxins; antigen–antibody complexes; inflammatory processes; and many others.
▪ IL-1 is carried by the blood to the thermoregulatory center in the hypothalamus, where
physiologic responses are initiated that result in fever.
Interferons (IFNs)
▪ Interferons are critical cytokines that play a key role in defense against virus infections
and other intracellular Organisms.
▪ Interferons are also immunoregulatory proteins capable of altering various cellular
processes, such as cell growth, differentiation, gene transcription, and translation.
▪ The IFN family consists of three types of interferons i.e. IFN-α, IFN-β and IFN-γ. IFN-γ
is produced by activated NK cells in innate immune responses and by specifically
sensitized T cells in adaptive immune responses.
▪ Moreover, the cytokines IL-2 and IL-12 can trigger T cells to produce IFN-γ.
▪ The IFN system consists of a series of events leading to protection of a cell from virus
replication………Block viral replication.
Adaptive Immunity
➢ The adaptive immune response can be antibody mediated
(humoral), cell mediated (cellular), or both.
➢ Unlike innate immunity, adaptive immunity is highly specific, has
immunologic memory, and can respond rapidly and vigorously to a
second antigen exposure.
Cellular Basis of the Adaptive Immune
Response
▪ Lymphoid progenitor cells evolve into two main
lymphocyte populations, B cells and T cells.
(eg, CD4 T cell, CD8 T cells).
▪ In the antibody-mediated arm, helper (CD4) T
lymphocytes recognize the pathogen’s antigens
complexed with class II MHC molecules on the surface
of an APC.
▪ Major host defense functions of antibodies include
neutralization of toxins and viruses, ADCC, and
opsonization of the pathogen.
▪ In the cell-mediated arm, the antigen–MHC class II
complex is recognized by helper (CD4) T lymphocytes,
while the antigen–MHC class I complex is recognized
by cytotoxic (CD8) T lymphocytes.
Schematic diagram of the cellular interactions in
the immune response.
Immuno lecs 5 8
Antigens
An antigen is substance that can provoke the production of an antibody. There are a wide
variety of features that largely determine immunogenicity.
Foreignness: Self and non self…….. Immunogenic
Size: In most cases, molecules with a molecular weight less than 10,000 are weakly
immunogenic, and very small ones (e.g. amino acids) are nonimmunogenic. Certain small
molecules (e.g. haptens) become immunogenic only when linked to a carrier protein.
Chemical and structural complexity: Amino acid homopolymers are less immunogenic
than heteropolymers containing two or three different amino acids.
Genetic constitution of the host:
➢ Two strains of the same species of animal may respond differently to the same antigen
because of a different composition of genes involved in the immune response (e.g.
different MHC alleles).
Dosage, route, and timing of antigen administration:
➢ Since the degree of the immune response depends on the amount of antigen given, the
immune response can be optimized by carefully defining the dosage (including
number of doses), route of administration, and timing of administration (including
intervals between doses).
➢ Finally, it should be noted that it is possible to enhance the immunogenicity of a
substance by combining it with an adjuvant. Adjuvants are substances that stimulate
the immune response by facilitating uptake into APCs.
Recognition of foreignness
➢ Distinguishing between self and nonself is essential in maintaining host integrity.
This distinction is highly specific and selective so as to eliminate invading
pathogens but not destroy host tissue.
➢ The modern use of tissue transplantation, where organs, tissues, and cells from
unrelated persons are carefully matched to the self-recognition markers on the
recipient’s cells when used in disease treatment.
The Major Histocompatibility Complex (MHC)
➢ (MHC) is a collection of genes on chromosome 6 in humans and chromosome 17
in mice. The MHC is also called the human leukocyte antigen (HLA) complex in
humans and the H-2 complex in mice.
➢ Almost all human cells contain HLA molecules on their plasma membranes.
➢ HLA molecules can be divided into three classes: class I molecules are found on all
types of nucleated body cells; class II molecules appear only on cells that can process
nonself materials and present antigens to other cells (i.e., macrophages, dendritic cells,
and B cells);
➢ Class III molecules include various secreted proteins that have immune functions.
Unlike class I and II MHC molecules, class III molecules are mostly secreted products
whose presence is not required to discriminate between self and nonself.
➢ Furthermore, the class III MHC molecules are not membrane proteins, are not related to
class I or II molecules, and have no role in antigen presentation.
➢ Each individual has two sets of MHC genes—one from each parent, and both are
expressed (i.e., they are codominant). Thus a person expresses many different HLA
products.
The MHC region of human chromosome 6 and the gene products
associated with each locus
➢ The HLA proteins differ among individuals; the closer two people are related,
the more similar are their HLA molecules.
➢ In addition, many forms of each HLA gene exist. This is because multiple
alleles of each gene have arisen by high gene mutation rates, gene
recombination, and other mechanisms (i.e., each gene locus is polymorphic).
➢ The differences in the HLA products expressed by individuals appear to
account for some of the variation in infectious disease susceptibility.
➢ Class I molecules comprise HLA types A, B, and C and serve to identify
almost all cells of the body as “self.”
➢ They also stimulate antibody production when introduced from one host into
another host with different class I molecules. This is the basis for MHC typing
when a patient is being prepared for an organ transplant.
➢ Class II HLA molecules are produced only by certain white blood cells, such as
activated macrophages, dendritic cells, mature B cells, some T cells, and certain
cells of other tissues.
➢ Class II molecules are required for T-cell communication with macrophages,
dendritic cells, and B cells.
➢ Part of the T-cell receptor must recognize a peptide within a class II molecule on
the antigen-presenting cell before the T cell can secrete cytokines necessary for
the immune response.
Class I MHC molecules
➢ MHC1 are transmembrane glycoproteins consist of a complex of two protein chains,
one with a mass of 45,000 Daltons (Da), known as the alpha chain, and the other
with a mass of 12,000 Da (β2-microglobulin).
➢ The alpha chain can be divided into three functional domains, designated α1, α2, and
α3. The α3 domain is attached to the plasma membrane by a short amino acid
sequence that extends into the cell interior, while the rest of the protein protrudes to
the outside.
➢ The β2-microglobulin (β2m) protein and α3 segment of the alpha chain are
noncovalently associated with one another and are close to the plasma membrane.
➢ The α1 and α2 domains lie to the outside and form the antigen-binding pocket.
Class II MHC molecules
➢ MHC11 are also transmembrane glycoproteins consisting of α and β chains of
mass 34,000 Da and 28,000 Da, respectively.
➢ Both chains combine to form a three dimensional protein pocket, the antigen-
binding pocket, into which a nonself peptide fragment can be captured for
presentation to other cells of the immune system.
➢ Although MHC class I and class II molecules are structurally distinct, both fold
into similar shapes.
➢ Each MHC molecule has a deep groove into which a short peptide derived from
a foreign substance can bind. Because this peptide is not part of the MHC
molecule, it can vary from one MHC molecule to the next.
Structure of MHC1 & MHC11 Proteins
The space-filling model of a class I MHC protein holding shorter peptide antigens (blue) than
does a class II MHC. (d)
➢ Foreign peptides in the MHC groove must be present to activate T cells, which in turn
activate other immunocytes.
➢ By binding and presenting foreign peptides, class I and class II molecules inform the
immune system of the presence of nonself.
➢ These peptides arise in different places within cells as the result of a process known as
antigen processing.
➢ Class I molecules bind to peptides that originate in the cytoplasm. Foreign peptides
within the cytoplasm of mammalian cells come from replicating viruses or other
intracellular pathogens, or the result of cancerous transformation.
➢ These intracellular antigenic proteins are digested by a cytoplasmic structure called the
proteasome, as part of the natural process by which a cell continually renews its protein
contents.
➢ The resulting short peptide fragments are pumped by specific transport proteins
from the cytoplasm into the endoplasmic reticulum.
➢ Within the endoplasmic reticulum the class I MHC alpha chain is synthesized
and associates with β2 microglobulin. This dimer appears to bind antigen as
soon as the foreign peptide enters the endoplasmic reticulum.
➢ The class I MHC molecule and antigenic peptide are then carried to, and
anchored in, the plasma membrane. In this way, the host cell presents the
antigen to a subset of T cells called CD8, or cytotoxic, T lymphocytes.
➢ CD8 T cells bear a receptor that is specific for class I MHC molecules that
present antigen, these T cells bind and ultimately kill infected host cells.
➢ Class II MHC molecules bind to fragments that initially come from antigens
outside the cell.
➢ This pathway functions with bacteria, viruses, and toxins that have been taken up
by endocytosis.
➢ APC, such as a macrophage, dendritic cell, or B cell, takes in the antigen or
pathogen by receptor mediated endocytosis or phagocytosis, and produces
antigen fragments by digestion in the phagolysosome.
➢ Fragments then combine with preformed class II MHC molecules and are
delivered to the cell surface.
Antigen-processing
pathways. (MHC
Class I and Class II)
Antigen Processing
and Presentation
➢ It is here that the peptide is recognized by CD4 T-helper cells.
➢ Unlike CD8 T cells, CD4 T cells do not directly kill target cells. Instead they
respond in two distinct ways.
➢ One is to proliferate, thereby increasing the number of CD4 cells that can react
to the antigen.
➢ Some of these cells will become memory T cells, which can respond to
subsequent exposures to the same antigen.
➢ The second response is to secrete cytokines (e.g., interleukin- 2) that either
directly inhibit the pathogen that produced the antigen or recruit and stimulate
other cells to join in the immune response.

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Immuno lecs 5 8

  • 1. Recognition of foreignness ➢ Distinguishing between self and nonself is essential in maintaining host integrity. This distinction is highly specific and selective so as to eliminate invading pathogens but not destroy host tissue. ➢ The modern use of tissue transplantation, where organs, tissues, and cells from unrelated persons are carefully matched to the self-recognition markers on the recipient’s cells when used in disease treatment. The Major Histocompatibility Complex (MHC) ➢ (MHC) is a collection of genes on chromosome 6 in humans and chromosome 17 in mice. The MHC is also called the human leukocyte antigen (HLA) complex in humans and the H-2 complex in mice.
  • 2. ➢ Almost all human cells contain HLA molecules on their plasma membranes. ➢ HLA molecules can be divided into three classes: class I molecules are found on all types of nucleated body cells; class II molecules appear only on cells that can process nonself materials and present antigens to other cells (i.e., macrophages, dendritic cells, and B cells); ➢ Class III molecules include various secreted proteins that have immune functions. Unlike class I and II MHC molecules, class III molecules are mostly secreted products whose presence is not required to discriminate between self and nonself. ➢ Furthermore, the class III MHC molecules are not membrane proteins, are not related to class I or II molecules, and have no role in antigen presentation. ➢ Each individual has two sets of MHC genes—one from each parent, and both are expressed (i.e., they are codominant). Thus a person expresses many different HLA products.
  • 3. The MHC region of human chromosome 6 and the gene products associated with each locus
  • 4. ➢ The HLA proteins differ among individuals; the closer two people are related, the more similar are their HLA molecules. ➢ In addition, many forms of each HLA gene exist. This is because multiple alleles of each gene have arisen by high gene mutation rates, gene recombination, and other mechanisms (i.e., each gene locus is polymorphic). ➢ The differences in the HLA products expressed by individuals appear to account for some of the variation in infectious disease susceptibility. ➢ Class I molecules comprise HLA types A, B, and C and serve to identify almost all cells of the body as “self.”
  • 5. ➢ They also stimulate antibody production when introduced from one host into another host with different class I molecules. This is the basis for MHC typing when a patient is being prepared for an organ transplant. ➢ Class II HLA molecules are produced only by certain white blood cells, such as activated macrophages, dendritic cells, mature B cells, some T cells, and certain cells of other tissues. ➢ Class II molecules are required for T-cell communication with macrophages, dendritic cells, and B cells. ➢ Part of the T-cell receptor must recognize a peptide within a class II molecule on the antigen-presenting cell before the T cell can secrete cytokines necessary for the immune response.
  • 6. Class I MHC molecules ➢ MHC1 are transmembrane glycoproteins consist of a complex of two protein chains, one with a mass of 45,000 Daltons (Da), known as the alpha chain, and the other with a mass of 12,000 Da (β2-microglobulin). ➢ The alpha chain can be divided into three functional domains, designated α1, α2, and α3. The α3 domain is attached to the plasma membrane by a short amino acid sequence that extends into the cell interior, while the rest of the protein protrudes to the outside. ➢ The β2-microglobulin (β2m) protein and α3 segment of the alpha chain are noncovalently associated with one another and are close to the plasma membrane. ➢ The α1 and α2 domains lie to the outside and form the antigen-binding pocket.
  • 7. Class II MHC molecules ➢ MHC11 are also transmembrane glycoproteins consisting of α and β chains of mass 34,000 Da and 28,000 Da, respectively. ➢ Both chains combine to form a three dimensional protein pocket, the antigen- binding pocket, into which a nonself peptide fragment can be captured for presentation to other cells of the immune system. ➢ Although MHC class I and class II molecules are structurally distinct, both fold into similar shapes. ➢ Each MHC molecule has a deep groove into which a short peptide derived from a foreign substance can bind. Because this peptide is not part of the MHC molecule, it can vary from one MHC molecule to the next.
  • 8. Structure of MHC1 & MHC11 Proteins
  • 9. The space-filling model of a class I MHC protein holding shorter peptide antigens (blue) than does a class II MHC. (d)
  • 10. ➢ Foreign peptides in the MHC groove must be present to activate T cells, which in turn activate other immunocytes. ➢ By binding and presenting foreign peptides, class I and class II molecules inform the immune system of the presence of nonself. ➢ These peptides arise in different places within cells as the result of a process known as antigen processing. ➢ Class I molecules bind to peptides that originate in the cytoplasm. Foreign peptides within the cytoplasm of mammalian cells come from replicating viruses or other intracellular pathogens, or the result of cancerous transformation. ➢ These intracellular antigenic proteins are digested by a cytoplasmic structure called the proteasome, as part of the natural process by which a cell continually renews its protein contents.
  • 11. ➢ The resulting short peptide fragments are pumped by specific transport proteins from the cytoplasm into the endoplasmic reticulum. ➢ Within the endoplasmic reticulum the class I MHC alpha chain is synthesized and associates with β2 microglobulin. This dimer appears to bind antigen as soon as the foreign peptide enters the endoplasmic reticulum. ➢ The class I MHC molecule and antigenic peptide are then carried to, and anchored in, the plasma membrane. In this way, the host cell presents the antigen to a subset of T cells called CD8, or cytotoxic, T lymphocytes. ➢ CD8 T cells bear a receptor that is specific for class I MHC molecules that present antigen, these T cells bind and ultimately kill infected host cells.
  • 12. ➢ Class II MHC molecules bind to fragments that initially come from antigens outside the cell. ➢ This pathway functions with bacteria, viruses, and toxins that have been taken up by endocytosis. ➢ APC, such as a macrophage, dendritic cell, or B cell, takes in the antigen or pathogen by receptor mediated endocytosis or phagocytosis, and produces antigen fragments by digestion in the phagolysosome. ➢ Fragments then combine with preformed class II MHC molecules and are delivered to the cell surface.
  • 13. Antigen-processing pathways. (MHC Class I and Class II) Antigen Processing and Presentation
  • 14. ➢ It is here that the peptide is recognized by CD4 T-helper cells. ➢ Unlike CD8 T cells, CD4 T cells do not directly kill target cells. Instead they respond in two distinct ways. ➢ One is to proliferate, thereby increasing the number of CD4 cells that can react to the antigen. ➢ Some of these cells will become memory T cells, which can respond to subsequent exposures to the same antigen. ➢ The second response is to secrete cytokines (e.g., interleukin- 2) that either directly inhibit the pathogen that produced the antigen or recruit and stimulate other cells to join in the immune response.
  • 15. Physical barriers in nonspecific (innate) resistance ➢ Many direct factors (nutrition, physiology, fever, age, genetics) and equally as many indirect factors (personal hygiene, socioeconomic status, living conditions) influence all host-microbe relationships. ➢ Physical and Mechanical Barriers ➢ Skin outer layer consists of thick, closely packed cells called keratinocytes, which produce keratins. Keratins are scleroproteins (i.e., insoluble proteins) that make up the main components of hair, nails, and the outer skin cells. ➢ These outer skin cells shed continuously, removing any grime or microorganisms that manage to adhere to their surface.
  • 16. ▪ The skin is slightly acidic (around pH 5 to 6) due to skin oil, secretions from sweat glands, and organic acids produced by commensal staphylococci. ▪ skin-associated lymphoid tissue (SALT). One type of SALT cell is the Langerhans cell, a specialized myeloid cell that can phagocytose antigens. ▪ The epidermis also contains another type of SALT cell called the intraepidermal lymphocyte.
  • 17. Mucous Membranes ▪ The mucous membranes of the eye (conjunctiva) and the respiratory, digestive, and urogenital systems withstand microbial invasion. ▪ Mucus contain lysozyme, an enzyme that lyses bacteria by hydrolyzing the bacterial cell wall peptidoglycan. ▪ Mucus contain IGA antibody ▪ They also contain significant amounts of the iron-binding protein, lactoferrin. Lactoferrin is released by activated macrophages and polymorphonuclear leukocytes (PMNs). ▪ Lactoferrin sequesters iron from the plasma, reducing the amount of iron available to invading microbial pathogens and limiting their ability to multiply.
  • 18. ▪ Mucous membranes produce lactoperoxidase, an enzyme that catalyzes the production of superoxide radicals, a reactive oxygen intermediate that is toxic to many microorganisms ▪ mucus-associated lymphoid tissue (MALT). There are several types of MALT e.g GALT, BALT ▪ The mucociliary apparatus for removal of bacteria in the respiratory tract is aided by the pulmonary macrophages. Special protective mechanisms in the respiratory tract include the hairs at the nares and the cough reflex, which prevents aspiration. ▪ In the gastrointestinal tract, several systems function to inactivate bacteria: Saliva contains numerous hydrolytic enzymes; the acidity of the stomach kills many ingested bacteria (eg, Vibrio cholerae), and the small intestine contains many proteolytic enzymes and active macrophages. Both factors can destroy microorganisms in the small intestine.
  • 19. ▪ Most mucous membranes of the body carry a constant normal microbiota that itself opposes establishment of pathogenic microorganisms (“bacterial interference”). ▪ For example, in the adult vagina, an acidic pH is maintained by normal lactobacilli, inhibiting establishment of yeasts, anaerobes, and gram-negative bacteria.
  • 20. Complement System ▪ The complement system includes serum and membrane bound proteins that function in both innate and adaptive host defense systems. ▪ The complement system proteins are synthesized by the liver, and circulate in the blood as inactive precursors. ▪ Several complement components are proenzymes, which must be cleaved to form active enzymes. The components are numbered from C1 to C9, and the reaction sequence is C1-C4-C2-C3-C5-C6-C7-C8-C9. ▪ Biologic Effects of Complement System ▪ Activation of complement results in four major outcomes: (1) cytolysis, (2) chemotaxis, (3) opsonization, and (4) anaphylatoxins.
  • 21. ▪ Cytolysis is the lysis of cells, such as bacteria, virus infected cells, and tumor cells. This process occurs through the development of the membrane attack complex (MAC) (C5b, 6, 7, 8, 9), which inserts into the membrane of an organism or cell. The MAC leads to loss of osmotic integrity and cell lysis. ▪ Chemotaxis is a process in which an immune cell, usually a phagocyte, is attracted to and moves toward a soluble factor. For example, C5a is a potent chemotactic agent that stimulates movement of neutrophils and monocytes toward sites of antigen deposition. ▪ Opsonization is a process in which microorganisms and antigen–antibody complexes become coated with molecules that bind to receptors on phagocytes. Phagocytosis is more efficient in the presence of C3b because of the presence of C3b receptors on phagocytes.
  • 22. ▪ Anaphylatoxins promote vasodilation and increased vascular permeability. Both C3a and C5a are potent promoters of vasodilation and vascular permeability. ▪ These two complement components also stimulate mast cells and basophils to release histamine. This function of complement results in an increased blood flow to the site of infection, allowing more complement, antibodies, and immune cells to enter the site of infection.
  • 23. Fever ▪ Fever is the most common systemic manifestation of the inflammatory response and is a cardinal symptom of infectious disease. The ultimate regulator of body temperature is the thermoregulatory center in the hypothalamus. ▪ Among the substances capable of inducing fever (pyrogens) are endotoxins of gram- negative bacteria and cytokines released from lymphoid cells, such as IL-1. ▪ Various activators can act upon mononuclear phagocytes and other cells and induce them to release IL-1. Among these activators are microbes and their products; toxins, including endotoxins; antigen–antibody complexes; inflammatory processes; and many others. ▪ IL-1 is carried by the blood to the thermoregulatory center in the hypothalamus, where physiologic responses are initiated that result in fever.
  • 24. Interferons (IFNs) ▪ Interferons are critical cytokines that play a key role in defense against virus infections and other intracellular Organisms. ▪ Interferons are also immunoregulatory proteins capable of altering various cellular processes, such as cell growth, differentiation, gene transcription, and translation. ▪ The IFN family consists of three types of interferons i.e. IFN-α, IFN-β and IFN-γ. IFN-γ is produced by activated NK cells in innate immune responses and by specifically sensitized T cells in adaptive immune responses. ▪ Moreover, the cytokines IL-2 and IL-12 can trigger T cells to produce IFN-γ. ▪ The IFN system consists of a series of events leading to protection of a cell from virus replication………Block viral replication.
  • 25. Adaptive Immunity ➢ The adaptive immune response can be antibody mediated (humoral), cell mediated (cellular), or both. ➢ Unlike innate immunity, adaptive immunity is highly specific, has immunologic memory, and can respond rapidly and vigorously to a second antigen exposure.
  • 26. Cellular Basis of the Adaptive Immune Response ▪ Lymphoid progenitor cells evolve into two main lymphocyte populations, B cells and T cells. (eg, CD4 T cell, CD8 T cells). ▪ In the antibody-mediated arm, helper (CD4) T lymphocytes recognize the pathogen’s antigens complexed with class II MHC molecules on the surface of an APC. ▪ Major host defense functions of antibodies include neutralization of toxins and viruses, ADCC, and opsonization of the pathogen. ▪ In the cell-mediated arm, the antigen–MHC class II complex is recognized by helper (CD4) T lymphocytes, while the antigen–MHC class I complex is recognized by cytotoxic (CD8) T lymphocytes. Schematic diagram of the cellular interactions in the immune response.
  • 28. Antigens An antigen is substance that can provoke the production of an antibody. There are a wide variety of features that largely determine immunogenicity. Foreignness: Self and non self…….. Immunogenic Size: In most cases, molecules with a molecular weight less than 10,000 are weakly immunogenic, and very small ones (e.g. amino acids) are nonimmunogenic. Certain small molecules (e.g. haptens) become immunogenic only when linked to a carrier protein. Chemical and structural complexity: Amino acid homopolymers are less immunogenic than heteropolymers containing two or three different amino acids.
  • 29. Genetic constitution of the host: ➢ Two strains of the same species of animal may respond differently to the same antigen because of a different composition of genes involved in the immune response (e.g. different MHC alleles). Dosage, route, and timing of antigen administration: ➢ Since the degree of the immune response depends on the amount of antigen given, the immune response can be optimized by carefully defining the dosage (including number of doses), route of administration, and timing of administration (including intervals between doses). ➢ Finally, it should be noted that it is possible to enhance the immunogenicity of a substance by combining it with an adjuvant. Adjuvants are substances that stimulate the immune response by facilitating uptake into APCs.
  • 30. Recognition of foreignness ➢ Distinguishing between self and nonself is essential in maintaining host integrity. This distinction is highly specific and selective so as to eliminate invading pathogens but not destroy host tissue. ➢ The modern use of tissue transplantation, where organs, tissues, and cells from unrelated persons are carefully matched to the self-recognition markers on the recipient’s cells when used in disease treatment. The Major Histocompatibility Complex (MHC) ➢ (MHC) is a collection of genes on chromosome 6 in humans and chromosome 17 in mice. The MHC is also called the human leukocyte antigen (HLA) complex in humans and the H-2 complex in mice.
  • 31. ➢ Almost all human cells contain HLA molecules on their plasma membranes. ➢ HLA molecules can be divided into three classes: class I molecules are found on all types of nucleated body cells; class II molecules appear only on cells that can process nonself materials and present antigens to other cells (i.e., macrophages, dendritic cells, and B cells); ➢ Class III molecules include various secreted proteins that have immune functions. Unlike class I and II MHC molecules, class III molecules are mostly secreted products whose presence is not required to discriminate between self and nonself. ➢ Furthermore, the class III MHC molecules are not membrane proteins, are not related to class I or II molecules, and have no role in antigen presentation. ➢ Each individual has two sets of MHC genes—one from each parent, and both are expressed (i.e., they are codominant). Thus a person expresses many different HLA products.
  • 32. The MHC region of human chromosome 6 and the gene products associated with each locus
  • 33. ➢ The HLA proteins differ among individuals; the closer two people are related, the more similar are their HLA molecules. ➢ In addition, many forms of each HLA gene exist. This is because multiple alleles of each gene have arisen by high gene mutation rates, gene recombination, and other mechanisms (i.e., each gene locus is polymorphic). ➢ The differences in the HLA products expressed by individuals appear to account for some of the variation in infectious disease susceptibility. ➢ Class I molecules comprise HLA types A, B, and C and serve to identify almost all cells of the body as “self.”
  • 34. ➢ They also stimulate antibody production when introduced from one host into another host with different class I molecules. This is the basis for MHC typing when a patient is being prepared for an organ transplant. ➢ Class II HLA molecules are produced only by certain white blood cells, such as activated macrophages, dendritic cells, mature B cells, some T cells, and certain cells of other tissues. ➢ Class II molecules are required for T-cell communication with macrophages, dendritic cells, and B cells. ➢ Part of the T-cell receptor must recognize a peptide within a class II molecule on the antigen-presenting cell before the T cell can secrete cytokines necessary for the immune response.
  • 35. Class I MHC molecules ➢ MHC1 are transmembrane glycoproteins consist of a complex of two protein chains, one with a mass of 45,000 Daltons (Da), known as the alpha chain, and the other with a mass of 12,000 Da (β2-microglobulin). ➢ The alpha chain can be divided into three functional domains, designated α1, α2, and α3. The α3 domain is attached to the plasma membrane by a short amino acid sequence that extends into the cell interior, while the rest of the protein protrudes to the outside. ➢ The β2-microglobulin (β2m) protein and α3 segment of the alpha chain are noncovalently associated with one another and are close to the plasma membrane. ➢ The α1 and α2 domains lie to the outside and form the antigen-binding pocket.
  • 36. Class II MHC molecules ➢ MHC11 are also transmembrane glycoproteins consisting of α and β chains of mass 34,000 Da and 28,000 Da, respectively. ➢ Both chains combine to form a three dimensional protein pocket, the antigen- binding pocket, into which a nonself peptide fragment can be captured for presentation to other cells of the immune system. ➢ Although MHC class I and class II molecules are structurally distinct, both fold into similar shapes. ➢ Each MHC molecule has a deep groove into which a short peptide derived from a foreign substance can bind. Because this peptide is not part of the MHC molecule, it can vary from one MHC molecule to the next.
  • 37. Structure of MHC1 & MHC11 Proteins
  • 38. The space-filling model of a class I MHC protein holding shorter peptide antigens (blue) than does a class II MHC. (d)
  • 39. ➢ Foreign peptides in the MHC groove must be present to activate T cells, which in turn activate other immunocytes. ➢ By binding and presenting foreign peptides, class I and class II molecules inform the immune system of the presence of nonself. ➢ These peptides arise in different places within cells as the result of a process known as antigen processing. ➢ Class I molecules bind to peptides that originate in the cytoplasm. Foreign peptides within the cytoplasm of mammalian cells come from replicating viruses or other intracellular pathogens, or the result of cancerous transformation. ➢ These intracellular antigenic proteins are digested by a cytoplasmic structure called the proteasome, as part of the natural process by which a cell continually renews its protein contents.
  • 40. ➢ The resulting short peptide fragments are pumped by specific transport proteins from the cytoplasm into the endoplasmic reticulum. ➢ Within the endoplasmic reticulum the class I MHC alpha chain is synthesized and associates with β2 microglobulin. This dimer appears to bind antigen as soon as the foreign peptide enters the endoplasmic reticulum. ➢ The class I MHC molecule and antigenic peptide are then carried to, and anchored in, the plasma membrane. In this way, the host cell presents the antigen to a subset of T cells called CD8, or cytotoxic, T lymphocytes. ➢ CD8 T cells bear a receptor that is specific for class I MHC molecules that present antigen, these T cells bind and ultimately kill infected host cells.
  • 41. ➢ Class II MHC molecules bind to fragments that initially come from antigens outside the cell. ➢ This pathway functions with bacteria, viruses, and toxins that have been taken up by endocytosis. ➢ APC, such as a macrophage, dendritic cell, or B cell, takes in the antigen or pathogen by receptor mediated endocytosis or phagocytosis, and produces antigen fragments by digestion in the phagolysosome. ➢ Fragments then combine with preformed class II MHC molecules and are delivered to the cell surface.
  • 42. Antigen-processing pathways. (MHC Class I and Class II) Antigen Processing and Presentation
  • 43. ➢ It is here that the peptide is recognized by CD4 T-helper cells. ➢ Unlike CD8 T cells, CD4 T cells do not directly kill target cells. Instead they respond in two distinct ways. ➢ One is to proliferate, thereby increasing the number of CD4 cells that can react to the antigen. ➢ Some of these cells will become memory T cells, which can respond to subsequent exposures to the same antigen. ➢ The second response is to secrete cytokines (e.g., interleukin- 2) that either directly inhibit the pathogen that produced the antigen or recruit and stimulate other cells to join in the immune response.