Immune Response: Innate & Adaptive Immunity

IMMUNE RESPONSE
Immunity refers to protection against infections. The immune system is the collection of cells and molecules that are
responsible for defending the body against the countless pathogens that individuals encounter. Defects in the immune system
render individuals easy prey to infections and are the cause of immunodeficiency diseases. But the immune system is itself
capable of causing tissue injury and disease, which are often referred to as hypersensitivity disorders.
Immune response is a complex of protective reactions, which helps organism to maintain antigenic peculiarities and cellular
homeostasis during contacts with external environment. Defense against pathogens consists of two types of reactions:
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Innate immunity (also called natural, non-specific, or native, immunity) is mediated by cells and proteins that are
always present (hence the term innate), poised to react against infectious pathogens. These mechanisms are called
into action immediately in response to infection, and thus provide the first line of defense. Some of these mechanisms
also are involved in clearing damaged cells and tissues. A major reaction of innate immunity is inflammation
– It acts against various antigens.
– It is genetically determined and is characteristic for species.
Adaptive immunity is normally silent and responds (or adapts) to the presence of infectious agents by generating
potent mechanisms for neutralizing and eliminating the pathogens. By convention, the terms immune system and
immune response generally refer to adaptive immunity. Many pathogens have evolved to resist innate immunity, and
protection against these infections requires the more specialized and powerful mechanisms of adaptive immunity (also
called acquired, or specific, immunity).
– Reactions are specific against antigen. Immune response is acquired by individual during its contacts with
various antigens.
– It can be:
• Humoral
• Cellular
CELLS AND TISSUES OF THE IMMUNE SYSTEM
The cells of the immune system consist of lymphocytes, most of which have specific receptors for antigens and mount adaptive
immune responses; specialized APCs, which capture and display microbial and other antigens to the lymphocytes; and various
effector cells, whose function is to eliminate microbes and other antigens.
Specific immune response cells
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T lympocytes (T helpers: Th1 and Th2, T cytotoxic cells, T memory cells)
B lymphocytes → plasma cells→ IgG, IgM, IgA, IgE, IgD B memory cells
Antigen presenting cells
o Dendritic cells
o Macrophages
o B cells
Lymphocytes
Although all lymphocytes are morphologically similar, they actually consist of several functionally and phenotypically distinct
populations. Lymphocytes develop from precursors in the generative (primary) lymphoid organs; T lymphocytes mature in the
thymus, whereas B lymphocytes mature in the bone marrow. Each T or B lymphocyte and its progeny, which constitute a
clone, express a single antigen receptor, and the total population of lymphocytes can recognize tens or hundreds of millions of
antigens. The enormous diversity of antigen receptors is encoded by variant DNA sequences that are created during lymphocyte
maturation by the joining and diversification of different gene segments to form functional antigen receptor genes, a process
that occurs only in B cells and T cells.
Receptors that are expressed in B cells are called antibodies, while their T-cell counterparts are called T-cell receptors. Mature T and
B lymphocytes recirculate through peripheral (secondary) lymphoid organs—the lymph nodes, spleen and mucosal tissues—and
reside in these organs and in most tissues. Foreign antigens are concentrated in these organs, where they bind to and activate the
clones of lymphocytes that express receptors for those antigens, a process known as clonal selection.
All mature lymphocytes go through distinct phases during their lives:
• naïve lymphocytes express antigen receptors but have not responded to antigens and do not serve any functions;
• effector lymphocytes are induced by lymphocyte activation and perform the functions that eliminate microbes; and
• memory lymphocytes, induced during activation, survive in a functionally silent state even after the antigen is eliminated and
respond rapidly upon subsequent encounters with the antigen.
T Lymphocytes
Thymus-derived T lymphocytes develop into the effector cells of cellular immunity and “help” B cells to produce antibodies
against protein antigens. T cells constitute 60% to 70% of the lymphocytes in peripheral blood and are the major lymphocyte
population in splenic periarteriolar sheaths and lymph node interfollicular zones. T cells cannot recognize free or circulating
antigens; instead, the vast majority (>95%) of T cells sense only peptide fragments of proteins displayed by molecules of the
major histocompatibility complex (MHC)*.
Because T cell antigen receptors have evolved to see MHC-bound peptides on cell surfaces, T cells only recognize antigens
presented by other cells. The outcome of this interaction varies dramatically
depending on the type of T cell that is involved and the identity of the other
interacting cell, ranging from the killing of virus-infected cells to the
activation of phagocytes or B lymphocytes that have ingested protein
antigens. Peptide antigens presented by MHC molecules are recognized by
the T-cell receptor (TCR), an heterodimer that in most T cells is composed of
disulfide-linked α and β protein chains. Each chain has a variable region
that participates in binding a particular peptide antigen and a constant
region that interacts with associated signalling molecules.
Major histocompatibility molecules
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The main physiologic function of the cell surface histocompatibility
molecules is to bind peptide fragments of foreign proteins for
presentation to T cells
Class MHC I and MHC II are cell surface glycoproteins involved in
antigen presentation
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Class MHC I molecules are expressed on all nucleated cells and platelets. It binds and displays peptides that are derived
from proteins ( for ex. viral antigens) synthesized within the cell. CD8+ cytotoxic cells can recognize peptides only
presented as a complex with self class I molecules.
Class MHC II molecules are expressed on antigen presenting cells. Class II molecules present exogenous antigens that
are first processed in the phagolysosomes. CD4+ can recognize peptides presented as a complex with self class II
molecules.
It is now known that the normal function of MHC molecules is to display peptides for recognition by CD4+ and CD8+ T
lymphocytes. In each person, T cells recognize only peptides displayed by that person’s MHC molecules, which, of course, are
the only MHC molecules that the T cells normally encounter. This phenomenon is called MHC restriction. The human MHC,
known as the human leukocyte antigen (HLA) complex, consists of a cluster of genes on chromosome 6
On the basis of their chemical structure, tissue distribution, and function, MHC gene products fall into two main categories:
• Class I MHC molecules are expressed on all nucleated cells and are encoded by three closely linked loci, designated
HLA-A, HLA-B, and HLA-C. Each of these molecules consists of a polymorphic α chain noncovalently associated with an
invariant β2- microglobulin polypeptide. In chain is where the foreign peptides bind to MHC molecules. In general, class
I MHC molecules bind and display peptides derived from protein antigens present in the cytosol of the cell (e.g., viral
and tumor antigens).
•
Class II MHC molecules are encoded by genes in the HLA-D region, which contains three subregions: DP, DQ, and DR.
Class II molecules are heterodimers of noncovalently linked α and β subunits. Unlike class I MHC molecules, which are
expressed on all nucleated cells, expression of class II MHC molecules is restricted to a few cell types, mainly APCs (notably,
dendritic cells), macrophages, and B cells.
Several other proteins are encoded in the MHC locus, including complement components (C2, C3, and Factor B) and the cytokines
tumor necrosis factor (TNF) and lymphotoxin.
B Lymphocytes
B (bone marrow–derived) lymphocytes are the cells that produce antibodies, the mediators of humoral immunity. B cells make up
10% to 20% of the circulating peripheral lymphocyte population. They also are present in bone marrow and in the follicles of peripheral
(secondary) lymphoid organs. B cells recognize antigen by means of membrane-bound antibody of the immunoglobulin M (IgM) class,
expressed on the surface together with signaling molecules to form the B-cell receptor (BCR) complex (Fig. 5.7). Whereas T cells
recognize only MHC-associated peptides, B cells recognize and respond to many more chemical structures, including soluble or cellassociated proteins, lipids, polysaccharides, nucleic acids, and small chemicals, without a requirement for the MHC. As with TCRs, each
antibody has a unique amino acid sequence. This sequence diversity is a consequence of the rearrangement and assembly of a
multitude of immunoglobulin (Ig) gene segments, a process that creates functional Ig genes. B cells express several invariant molecules
that are responsible for signal transduction and B-cell activation.
After stimulation, B cells differentiate into plasma cells, which secrete large amounts of antibodies. There are five classes, or isotypes,
of immunoglobulins: IgG, IgM, and IgA constitute more than 95% of circulating antibodies. IgA is the major isotype in mucosal
secretions; IgE is present in the circulation at very low concentrations and also is found attached to the surfaces of tissue mast cells;
and IgD is expressed on the surfaces of B cells but is secreted at very low levels. These isotypes differ in their ability to activate
complement and recruit inflammatory cells, and thus have different roles in host defense and disease states.
Natural Killer Cells and Innate Lymphoid Cells
NK cells are lymphocytes that arise from the same common lymphoid progenitor that gives rise to T lymphocytes and B lymphocytes.
However, NK cells are innate immune cells, as they are functional without prior activation and do not express highly variable and
clonally distributed receptors for antigens. Instead, NK cells have two types of receptors—inhibitory and activating. Inhibitory
receptors recognize self class I MHC molecules, which are expressed on all healthy cells, whereas activating receptors recognize
molecules that are expressed or upregulated on stressed or infected cells. Normally, the effects of inhibitory receptors dominate over
those of activating receptors, preventing spontaneous activation of the NK cells. Infections (especially viral infections) and stress are
associated with reduced expression of class I MHC molecules and increased expression of proteins that engage activating receptors.
The net result is that the NK cells are activated and the infected or stressed cells are killed and eliminated.
NK cells also secrete cytokines such as interferon-γ (IFN-γ), which activates macrophages to destroy ingested microbes, and thus NK
cells provide early defense against intracellular microbial infections. Innate lymphoid cells (ILCs) are populations of lymphocytes that
lack TCRs but produce cytokines similar to those that are made by T cells.
Lymphoid organs
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Central or primary lymphoid organs
o Bone marrow and thymus
Peripheral or secondary lymphoid organs
o Lymph nodes,spleen, gut associated lymphoid tissue, mucosa associated lymphoid tissue
The peripheral lymphoid organs are the site of lymphocytes activation by antigen
.
Lymph node
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Lymphatics drain extracellular fluid (or lymph) from peripheral tissues, through lymph nodes
Lymph carries antigen and antigen bearing cells to the lymph nodes
Spleen
Red pulp – RBC destruction
White pulp
• Periarteriolar lymphoid sheath _ T lymphocytes
• Follicles_B lymphocytes
NB!
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Spleen collects antigen from the blood
Lymph nodes collects antigen from sites of infection of tissues
Barriers against infection
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The simplest way to avoid infection is to prevent the microorganism to enter the organism. Body surface is protected by
epithelium:
o Skin
o Mucous membranes in gastrointestinal, respiratory, and urinogenital tracts
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1.Innate Immunity
The major components of innate immunity are epithelial barriers that block the entry of microbes, phagocytic cells (mainly
neutrophils and macrophages), dendritic cells (DCs), natural killer (NK) cells and other innate lymphoid cells, and several plasma
proteins, including the proteins of the complement system.
Phagocytes, dendritic cells and many other cells, such as epithelial cells, express receptors that sense the presence of infectious
agents and substances released from dead cells.
Receptors of Innate Immunity
Pattern recognition receptors are located in all the cellular compartments where pathogens may be present: plasma membrane
receptors detect extracellular pathogens, endosomal receptors detect ingested microbes, and cytosolic receptors detect
microbes in the cytoplasm
Cellular receptors for microbes and products of cell injury. Phagocytes, dendritic cells, and many types of epithelial cells express different classes
of receptors that sense the presence of microbes and dead cells. Toll-like receptors (TLRs) located in different cellular compartments, as well as
other cytoplasmic and plasma membrane receptors, recognize products of different classes of microbes. The major classes of innate immune
receptors are TLRs, NOD-like receptors in the cytosol (NLRs), C-type lectin receptors, RIG-like receptors for viral RNA, named after the founding
member RIG-I, and cytosolic DNA sensors
Reactions of Innate Immunity
The innate immune system provides host defense by the following two main reactions:
• Inflammation. Cytokines and products of complement activation, as well as other mediators, are produced during
innate immune reactions and trigger the vascular and cellular components of inflammation. The recruited leukocytes
destroy pathogens and ingest and eliminate damaged cells.
• Anti-viral defense. Type I interferons produced in response to viruses act on infected and uninfected cells and activate
enzymes that degrade viral nucleic acids and inhibit viral replication.
2.Adaptive Immunity
The adaptive immune system consists of lymphocytes and their products, including antibodies. In contrast to the limited
repertoire of the innate immune system, the adaptive immune system can recognize a vast array of foreign substances.
There are two types of adaptive immunity:
• Humoral immunity, mediated by soluble proteins called antibodies that are produced by B lymphocytes (B cells)
• Cell-mediated (or cellular) immunity, mediated by T lymphocytes (also called T cells).
Antibodies provide protection against extracellular pathogens in the blood, mucosal surfaces, and tissues. T lymphocytes are
important in defense against intracellular microbes. They work by either directly killing infected cells (accomplished by cytotoxic
T lymphocytes) or by activating phagocytes to kill ingested microbes, via the production of soluble protein mediators called
cytokines (made by helper T cells). We next turn to the main properties and functions of the cells of the immune system.
Humoral immune response
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Humoral immunity is mediated by antibodies, which are produced by plasma cells deriving from B lymphocytes
It eliminates extracellular microbes and microbial toxins (neutralization, opsonization, complement system activation).
Antibodies : IgA, IgE, IgD, IgG, IgM
Activation of naÏve T cells requires 2 independent signals
1.Binding of peptid-MHC complex by T cell receptor
2.Co-stimulatory signal delivered by the same APC
Cytotoxic cells requires:
1. Activation by dendritic cell
2. Requires presence of CD4Tcells
TH2 drives B cells to differentiate to plasma cells and produce Ig
Immune granulomas
• Certain microorganisms having been phagocytosed by macrophages avoid intracellular killing and survive
• In such case T helpers are producing gamma interferon or other macrophage activating factor
• Immune granuloma will be formed in places where persistent antigen or toxic materials occurs
Composed of
• Epitheliod cells – derived from macrophages
• Giant cells – formed by fusion of macrophages
• Necrosis – caused by lysosomal enzymes released by macrophages or cytotoxic materials as TNF
• Lymphocytes
• Other cells : can be also plasma cells, neutrophils, eosinophils
Formation of Immune Granulomas
induce:
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Mycobacterium tuberculosis
Treponema pallidum
Mycobacterium leprae
Yersinia pseudoturbeculosis
Echinococcus
Foreign body granuloma
Epithelial barriers against infection
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Mechanical:
o Epithelial cells joined by thight junctions,
o Longitudinal flow of air or fluid across epithelium,
o Movement of mucous by cilia
Chemical:
o Fatty acids (skin), lysozyme (saliva, tears, sweat), low pH (stomach)
Microbiological:
o Antagonism associated with normal flora of the body.
INFLAMATOIN, COMPLEMENT SYSTEM (CHPTR 3, lo q he estado metiendo es del chptr 5)
Inflammation
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Inflammation is a complex of vascular reactions in the connective tissue to the exogenous and endogenous injurious
agents like:
o Biological
o Chemical
o
Physical
The reaction of blood vessels leads to the accumulation of fluid and leucocytes in extravascular tissues.
The main protective mechanism in inflammation is phagocytosis
Inflammation at the site of infection is initiated by the response of macrophage to pathogen:
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Secretion of cytokins (IL1, TNF-alfa, IL6, IL8, IL12;
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Engulfing and formation of phsgolysosomes to digest pathogen
Antigen presentation
Complement system
Complement system is made up of a large number of distinct plasma proteins that is activated (via classical, MB-lectin,
alternative patways) to induce series of inflammatory responses by activation of C3 convertase to split C3:
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C3a, C5a increases vascular permeability, phagocyte recruitment, activates mast cells
C3b Opsonization of pathogens
C5b, C6-9 Membrane attack complex for cell lysis
Infammation (deep)
The inflammatory response involves vascular and cellular events mediated by variuos mediators.
• Cytokines produced by macrophages,
• Plasma factors (produced by liver) – acute phase proteins, complement system, kinin system, coagulation factors…
• Vasoactive amines – histamine (mast cells, platelets, basophils); serotonin (platelets); causes dilatation of arterioles and
increases permeability of venules.
• Arachidonic acid metabolites – prostaglandins and thromboxane (cyclooxygenase pathway) leukotriens (lipoxygenase
pathway)
• The signs of inflammation by Celsus (25 BC—50 AD)
o Rubor
o Tumor
o Calor
o Dolor
by Virchow:
o Functio laesa
Vascular phase:
• Vasoconstriction
• Vasodilatation-involves arterioles and opening of capillary beds in the area
• Increased vascular permeability due to formation of endothelial gaps in the venules of microcirculation
• Increased vascular permeability
• Exudation of fluid from capillaries helps:
o Dilute toxic or irritating agents
o To bring antibodies, complement, leukocytes...
o To bring antigen presenting cells to lymphoid organs
• Edema – denotes an excess of fluid (exudate or transudate) in the interstitial tissue
• An exudate is an inflammatory extravascular fluid that has a high protein concentration, much cellular debris, and a
specific gravity above 1.020.
• A transudate is a fluid with low protein content, most albumin, and specific gravity less than 1.012. It results from
hydrostatic imbalance across vascular endothelium, while permeability of endothelium is normal
Leukocytic events in inflammation:
A. Migration
• In the lumen of the vessel: margination, rolling, adhesion
• Transmigration across endothelium
• Migration in interstitial tissues toward a chemotactic agent
B. Phagocytosis
• Recognition and attachment (opsonization by C3b, IgG)
• Engulfment and formation phagosome and phagolysosome
• Killing or degradation by toxic oxygen nitrogen products, lysozymes, proteases etc
According to the exudate inflammation is classified in:
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Serous inflammation (inflammatio serosa)
Purulent inflammation (inflammatio purulenta)
Fibrinous inflammation (inflammatio fibrinosa):
Hemorrhagic inflammation (inflammatio haemorrhagica)
Serous inflammation (inflammatio serosa)
Exudate is transparent with small amount of desquamated epithelium or mesothelium
Causes: viruses (blisters in herpetic infection), physical agents
Catarrhal inflammation (inflammation catarrhalis) is a serous inflammation in mucous membranes. Catarrhus of upper
respirotary tract – rhinitis, nasopharingitis
Outcomes- healing or progress to other type, most commonly purulent
Purulent inflammation (inflammatio purulenta)
Pus or purulent exudate consists of neutrophils, necrotic cells, bacteria, plasma proteins
Causes – pyogenic bacteria (staphylococcus, streptococcus, Neiseria meningitidis, Neiseria gonorrhoeae)
Forms of purulent inflammation
• Abscess (it has pyogenic capsule)
• Phlegmone
• Empyema
Outcomes: Healing; Abscessus can drain through fistula; when tissue defect large – formation of connective tissue or scarring;
can develop sepsis; in chronc inflammation can develop amyloidosis;
Fibrinous inflammation (inflammatio fibrinosa)
When is greater vascular permeability larger molecules such as fibrinogen passes the vascular barrier and fibrinogen is
converted to fibrin
Causes – bacteria (streptococcus pneumonia, corynebacterium diphteriae, mycobacteria tuberculosis, shigella dysenteriae),
toxic agents (uraemia)
Fibrinous inflammation can be in serous body cavities lined by mesothelium, mucous membranes, and parenchymal organs
(lungs)
Fibrinous inflammation is classified:
• Fibrinous inflammation. It occures in serous body cavities and lungs
• Fibrinous ulcerative (dyphteric or pseudomembraneous inflammation); it develops in diphteria, dysentery, uremia,
Outcomes – resolution (fibrinous exudate removed by fibrinolysis, and other debris by macrophages; can be restored normal
tissue structure); organisation (fibrinous exudate is converted to connective tissue; it leads to synechiae or adhesion formation
in serous cavities, can develop obliteration of the cavity);
Fibrinous ulcerative inflammation in respiratory tract can lead to asphyxia;
Fibrinous ulcerative inflammation leads to scarring of mucous linings.
Haemorrhagic inflammation
Haemorrhagic inflammation (inflammation haemorrhagica) – exudate with great amount of RBC.
Haemorrhagic feature can have other types of inflammation (serous, fibrinous) when is other pathological states affecting small
vessels; It can be in vit. C deficiency, thrombocytopenia
Causes: viruses, bacterial toxins (antrax, pestis); medicines
Outcomes depends on the main disease
Examination Program
1. Morphogenesis of inflamation, its morphological manifestations, course,
outcomes and significance.
2. Causative factors of the serous and fibrinous inflammation, morphological
manifestations, outcomes and significance.
3. Causative factors of the purulent inflammation, morphological manifestations,
outcomes and significance.
4. Morphological manifestations of the specific immune reactions and
immunogenesis.
5. Morphology, outcomes and significance of peculiar specific immune response
(immune granulomas).
6. Morphological peculiarities of the tuberculous and other kinds of immune
granulomas.
7. Hyperergic immune reactions, its types and morphological peculiarities.
8. Classification of the immunodeficiencies, its morphological manifestations and
significance.
9. Amyloidosis, its essence and pathogenesis, classification, morphology and
significance.
10. Anemias, its classiffication, pathogenesis, general and pecular morphological
features of various forms, complications and causes of death.
11. Neutropenia (agranulocytosis), thrombocytopenia, its pathogenesis,
morphology, complications and causes of death.
12. Myeloid neoplasms, its classification, morphology, complications and causes
of death.
13. Lymphoid neoplasms, its classification, morphology, complications and causes
of death.
14. Hodgkin lymphoma, its morphology, complications and causes of death.
15. Radiation disease, its morphology, complications and causes of death.
For lab:
Self – learning questions
What is the immune response?
Enumerate the factors and phenomena of the immune response which prevent the
antigen getting into the internal environment and which are under way its getting
inside.
What is the classification of immune cells?
What is the classification of the immune system organs?
What is inflammation?
What is the main protective mechanism of inflammation?
Enumerate the main phases of phagocytosis.
What is the role of mast cells and granulocytes in inflammation?
Enumerate the main groups of mediators of inflammation.
What are the phases of inflammation?
What forms inflammatory infiltration?
Enumerate the main clinico-morphological features of inflammation. What
determines it?
46 (2012)
What is the possible outcome of inflammation?
What is chronical inflammation?
What do lymphocytes and plasma cells indicate at the site of inflammation?
What medical terms are used for characterization of inflammation?
What is serous exudate formed of?
What are the most frequent etiological factors of fibrinous inflammation?
What are the forms of fibrinous inflammation?
What components form purulent exudate?
What are the forms of purulent inflammation?
What is abscess, phlegmona, empyema?
What is furunculus, carbunculus?
What is the outcome of purulent inflammation?
What is catarrhal inflammation?
What are the components of catarrhal exudate?
When is hemorrhagical inflammation in process?