Download Methodological Instruction to Practical Lesson № 4

MINISTRY OF PUBLIC HEALTH OF UKRAINE
BUKOVINIAN STATE MEDICAL UNIVERSITY
Approval on methodological meeting
of the department of pathophisiology
Protocol №
Chief of department of the pathophysiology,
professor
Yu.Ye.Rohovyy
“___” ___________ 2008 year.
Methodological Instruction
to Practical Lesson
Мodule 1 : GENERAL PATHOLOGY.
Contenting module 1. General nosology.
Theme4: : Pathophysiology of the immune system.
Chernivtsi – 2008
1.Actuality of the theme. Immune insufficiency is to be considered as
an anomalous condition of immune system. The displays of these insufficiencies
are quite various: rise of sensitivity to bacterial and viral infections, development
of autoimmune diseases. Its clinical displays are determined by defeating of a
certain link of immune response. Nowadays there are description and
classifications of innate primary immunodeficiency conditions, which are
observed in children's age. There also are secondary immunodeficiency
syndromes, which are conditions of acquired nature, which arise under influence
of environment. Diagnostic of immune insufficiency is complicated, because there
are no specific symptoms, or clear parallelism between clinical symptoms and
laboratory confirmation. Illness masks and has manifestation similar various
clinical symptoms.
2.Length of the employment – 2 hours.
3.Aim:
To khow two variants of the immune response: thymus non dependend and
thymus dependend.
To be able: To analyse of the pathology of immune system
Functional stress of im.
system in maintenance
of antigenic hemostasis.
Disorder of immunocomponent
tissue structure and function.
Hypertensivsty
Pathologic tolerance
Allergy
Immunodeficiency
Reaction “graft-versus host”
To perform practical work: to analyse the pathogenesis of the AID
4. Basic level.
The name of the previous disciplines
1. histology
2. biochemistry
3. physiology
The receiving of the skills
Immunity. Cellular and humoral
mechanisms of immunity. Lymphocytes,
their populations and subpopulations.
Functions of lymphocytes.
Immunoglobulines and their classes
Functions of immune system
5. The advices for students.
1. Characterize immune response.
A. Immunity is a state of protection, primarily against infectious agents,
characterized by memory and specificity.
B. Antigens are chemical substances that react with preformed components of
the immune response. Immunogens are antigens that can also induce an immune
response. Haptens are antigens that cannot be immunogenic unless they are bound
to lager molecules called carriers.
C. Self-antigens are antigens on host cells. Self-antigens are normally not
recognized as immunogenic by the host’s immune systems, a condition known as
tolerance.
2. Describe induction of immune response.
A. The immune response is characterized by the activation of two types of
immunocytes: B lymphocytes (B cells) and T lymphocytes (T cells). The activities
of B cells compose the humoral immune response, and those of T cells make up
the cell-mediated immune response.
B. A B cell develops from a stem cell that matures under hormonal control in
bursal-equivalent tissues and develops into a mature plasma cell capable of
producing antibody against a specific antigen.
C. Antibodies are plasma glycoproteins that can be classified by chemical
structure and biologic activity as IgG, IgM, IgA, or IgD.
D. Antibodies may protect the host from harmful antigens by recognizing and
binding with the antigen’s antigenic determinant sites. Occupied antigenic
determinants on viruses and bacterial toxins are unable to bind with receptors on
host cells and are therefore unable to have injurious effects.
E. The protective effects of antibodies vary with the identity of the antigen.
Antibodies opsonize bacteria, neutralize toxins and viruses, and activate
inflammatory processes.
F. Antibodies of the systemic immune system function internally in the
bloodstream and tissues. Antibodies of the secretory, or mucosal, immune system
function externally in the secretions of mucous membranes.
G. A T cell develops from a stem cell that matures under hormonal control in the
thymus and develops into a cytotoxic T cell, which can kill target cells directly; a
delayed hypersensitivity T cell, which produces lymphokines that affect other cells
(especially macrophages); a helper T cell, which induces B cells to produce
antibody; or a suppressor T cell, which suppresses antibody production and
immune function.
H. Antibody production is the final stage of a process requiring the interaction of
B cells, helper T cells, and antigen-presenting cells.
I. The body actually recognizes that a substance is foreign through
histocompatibility antigens (or human leukocyte antigens). These antigens are
proteins found on the surface of nearly every cell in the body. The major group of
genes producing the HLA antigens is the HLA complex or the major
histocompatibility complex (MHC).
J. The HLA complex consists of four closely linked loci located on the short arm
of chromosome 6, known as the A, B, C, and D complex. The antigens produced
by the A, B, and C loci (class I antigens) are found on the surface of virtually all
cells except erythrocytes. The D complex consists of three separate and
independent loci (DR, DP, and DQ) and are confined mostly to B cells,
macrophages, some epithelial cells and some stimulated T lymphocytes.
3. Describe humoral and cell-mediated immune response.
3.1. Humoral Immune Response:
A. The bursa of Fabricius responsible for the maturation of B lymphocytes in
birds is not a distinct tissue in humans. Humans do have tissues, probably the bone
marrow, that make up the human bursal equivalent.
B. According to clonal selection theory, a large number of B cells with plasma
membrane receptors for all potential antigenic determinants are spontaneously
generated during fetal life.
C. The immune response is initiated when an antigen binds and interacts with
receptors on the surface of the immature B cell, triggering it into a sequence of
proliferation and differentiation that results in the production of (1)
immunoglobulin-secreting plasma cells and (2) a set of long-lived memory cells.
D. Antibodies are immunoglobulins known to have specificity for a particular
antigen. The five classes of immunoglobulins are IgG, IgA, IgM, IgE, and IgD.
E. The antigen-binding fragment (Fab) of the antibody contains the receptors for
antigenic determinants and confer specificity. The crystalline fragment (Fc) is
responsible for most of the biologic functions of the molecule.
F. The chief functions of antibodies are to protect the host by (1) neutralizing
bacterial toxins, (2) neutralizing viruses, (3) opsonizing bacteria (promoting
phagocytosis), and (4) activating components of the inflammatory response.
G. Most humoral immune response are polyclonal; however, the generation of
monoclonal antibodies – a single antibody of known specificity is generated rather
than a mixture of different antibodies – is creating new therapeutic and diagnostic
possibilities. A clinician can order tests for viral antigens that are specific and
diagnostic and detect the disease early in its course.
3.2. Cell-Mediated Immune Response:
A. T lymphocytes are responsible for cell-mediated immunity. There are five
types of mature T cells including memory cells, lymphokine-producing cells,
cytotoxic cells (Tc), helper T (Th) cells, and suppressor (Ts) cells. T cells mature
in the thymus and produce plasma membrane receptors specific for antigens.
B. In the thymus, T cells begin producing new proteins that are differentiation
related – called cluster of differentiation (CD) proteins (antigens) – that are
inserted into the plasma membrane of the cell. Several important CD proteins
participate in the development of the immune response.
C. The major effects of the cell-mediated immune response include cytotoxicity,
delayed hypersensitivity, memory, and control.
D. The NK cell appears to be related to the T cell lineage. The NK cell can
recognize yet undefined chemical changes on the surface of virally infected cells or
malignant cells and kill the infected or malignant cells by mechanisms similar to
the Tc cell.
4. Characterize cellular interaction in immune response.
Cellular Interactions in Immune Response
A. Antigens that cannot induce the immune response independently must first
interact with populations of cell, including T helper cells, macrophages (as antigenpresenting cells), and cytokines.
B. Cytokines are proteins or glycoproteins secreted by cells participating in the
immune response. They function as messengers, enabling communication among
macrophages and lymphocytes.
C. When an antigen enters a host, it first equilibrates throughout body fluids.
Eventually, antigen encounters macrophages, for example, by circulating through
interstitial spaces in the lymph node. At this point, antigen processing occurs.
D. For antigen presentation to lymphocytes to occur, it must be in a complex
with molecules of class I HLA antigens or class II HLA antigens. For Th cells to
respond, the antigen must be presented in a complex with class II HLA antigens
(HLA-DR, DP, or DQ). For Tc cells and Ts cells to respond, the antigen must be
presented in a complex with class I HLA antigens. During antigen presentation, IL1 is released by the macrophage and binds to receptors IL-2. IL-4 most likely
provides a signal to begin differentiation and proliferation of B lymphocytes or
antibody production.
5. Describe the forms of changes and disorders of immune system.
Forms of changes and disorders of immune system
Functional stress of immune system in maintenance of antigenic homeostasisimmunization, immune reactions
Disorder of immunocompetent tissue structure and function
Immunodeficiency
Pathological tolerance
Reaction «graft-versus host»
Typical forms of allergy
Disturbances of immune reactions, connected with disorders of systems,
functionally attended by immune system –
6. Characterize immunodeficiencies; describe examples of congenital or
primary diseases.
Immune deficiencies occur because of impaired function of one or more
components of the immune or inflammatory response. B cells, T cells, phagocytic
cells, or complement may be involved. The clinical manifestation of immune
deficiency is a tendency to develop unusual or recurrent severe infections.
Deficiencies in T cell immune responses are suspected when recurrent infections
are caused by certain viruses, fungi, and yeasts, or certain atypical organisms. B
cell deficiencies are suspected if the individual has recurrent infections with
encapsulated bacteria or viruses against which humoral immunity is normally
effective.
It may be unsafe to administer conventional immunizing agents or blood
products to many immunologically compromised individuals because of the risk
that the immunizing agent will cause an uncontrolled infection. Uncontrolled
infection is particularly a problem when attenuated vaccines that contain live, but
weakened microorganisms. Microorganisms against smallpox is an example of
such a vaccine. Although the virus is attenuated enough to be destroyed by a
normal immune system, it can survive, multiply, and cause severe disease in an
immunodeficient recipient.
Individual with immune deficiencies is also at risk for graft-versus-host disease.
This occurs if T cells in transfused blood are mature and capable of the cellmediated destruction of tissues in the graft recipient. The grafted T cells are
controlled by normal immune systems and no tissue destruction occurs. If the
recipient’s immune system is deficient, the grafted T cells will attack the
recipient’s tissue.
Congenital or primary immune deficiency occurs if lymphocyte development
is disturbed in the fetus or embryo or if there is a genetic anomaly. Some diseases
are primarily caused by a defect in one or the other of the cell lines although both T
and B cell lines may be partially deficient.
Severe combined immune deficiencies (SCID) occur when a common stem cell
for all white blood cells is absent. Therefore, T cells, B cells, and phagocytic cells
never develop. Most children with SCID caused by reticular digenesis, the most
severe SCID form, die in utero or very soon after birth. Many individuals with
SCID are deficient only in a stem cell for lymphocyte development rather than for
all white blood cells, as in reticular dysgenesis, and therefore have normal numbers
of all other white cells. T and B lymphocytes are few or totally absent in the
circulation, the spleen, and lymph nodes. The thymus is usually underdeveloped.
IgM and IgA levels are absent or greatly reduced; however, IgG levels may be
almost normal because of the presence of maternal antibodies. Other forms of
SCID are caused by autosomal recessive enzymatic defects that result in the
accumulation of toxic metabolites to rapidly dividing lymphocytes.
Di George syndrome is the complete lack, or more commonly partial lack, of
the thymus. This thymus deficiency causes lymphopenia and great decreased T cell
numbers and function.
Bruton agammaglobulinemia syndrome is caused by failure of B cell
precursors to become mature B cells because of the lack of normal bursalequivalent tissue. There are no circulating B cell, though T cell numerous and
function. Some immune deficiencies involve a defect that results in depressed
development of a small portion of the immune system. An example is Wiskott-
Aldrich syndrome, an X-linked recessive disorder, in which IgM antibody
responses against polysaccharide antigens from bacterial cell walls are deficient.
Another common defect in which a particular class of antibody is affected is
selective IgA deficiency. Individuals with selective IgA deficiency are able to
produce other classes of immunoglobulin but fail to produce IgA. Individuals with
IgA deficiency frequently present with chronic intestinal candidiasis. IgA may
normally prevent the uptake of allergens from the environment. Therefore IgA
deficiency may lead to increased allergen uptake and a more intense challenge to
the immune system because of prolonged exposure to environmental antigens.
7. Cite causes and consequences of acquired or secondary immune
deficiencies.
Acquired or secondary immune and inflammatory deficiency develops after birth
and is not related to genetic defects. Nutritional deficits in calorie or protein intake
can lead to deficiencies in T cell function and numbers. The humoral immune
response is less affected by starvation, although complement activity, neutrophils
chemotaxis, and bacterial killing by neutrophils are frequently depressed. Enzyme
cofactors, such as zinc and vitamins, may result in severe depressions of both B
and T cell function.
Iatrogenic disorders are caused by some form of medical treatment. Cancer
chemotherapeutic agents suppress blood cell formation in the bone marrow.
Immunosuppressive corticosteroids for treatment of individuals with transplants or
autoimmune diseases depress B and T cell formation. The consequence of these
therapies for cancer and immunosuppression is manifested as a progressive
increase in infections with opportunistic microorganisms.
Traumatized burn victims are susceptible to severe bacterial infections because
of decreased neutrophil function and complement levels. Burn victims also have
increased suppressor cell function, which may increase antigen-specific
suppression.
A relationship between emotional stress and depressed immune function seems
to exist. Many lymphoid organs are innervated and can be affected by nerve
stimulation. Also, lymphocytes have receptors for many hormones such as
neurotransmitters and can respond to changing levels of these chemicals with
increased or decreased function.
8. Describe the best known acquired immune deficiency disorder, AIDS.
AIDS is caused by a virus currently named human immunodeficiency virus or
HIV. The virus was isolated by researchers at the National Institute of Health as
the human T lymphotropic virus type III or HLV-111 and earlier by the Pasteur
Institute as the lymphadenopathy/AIDS virus or LAV. At least one other AIDSvirus (HIV-2) has been identified.
HIV is retrovirus carrying genetic information in RNA rather than DNA.
Retroviruses infect cells by binding a target cell through a surface receptor and
inserting their RNA into the target cell. A viral enzyme, reverse transcriptase,
converts the viral RNA to DNA and inserts that DNA into the infected cell’s
genetic material. Viral proliferation may occur resulting in the lysis and death of
the infected cell. If, however, the cell remains relatively dormant rather than active,
the viral genetic material integrated into the infected cell’s DNA may remain latent
for years, if not for the life of the individual.
CD4 is an antigen on the surface of cells that acts as a receptor for the HIV. The
virus primarily infects CD4-positive T helper lymphocytes but it may also infect
and lyze various other cells that express the CD4 antigen.
At the time of diagnosis, the individual may manifest one of four different
conditions: serologically negative, serologically positive but asymptomatic, early
stages of HIV disease, or AIDS. The currently accepted Centers for Disease
Control definition of AIDS relies on both laboratory tests and clinical symptoms.
The most common laboratory test is for antibodies against HIV. Without a positive
test for antibodies, individuals can be diagnosed as having AIDS if they have a
lymphoma of the brain and are less than 60 years of age or if they have lymphoid
interstitial pneumonitis and are less than 13 years of age. If they are seropositive,
the diagnosis of AIDS is made in association with a variety of clinical symptoms.
These include disseminated coccidioidomycosis or histoplasmosis, extrapulmonary
tuberculosis, persistent isosporiasis, recurrent salmonella septicemia, recurrent
bacterial infections, HIV encephalopathy, HIV wasting syndrome, lymphoma of
the brain at any age, non-Hodgkin lymphoma, and uterine cervical cancer. Other
clinical symptoms of AIDS include persistent lymphadenopathy, weight loss,
recurrent fevers, neurologic abnormalities with dementia in late stages, recurrent
pulmonary infiltrates, and the development of opportunistic infections such as
Pneumocystis carinii pneumonia and other atypical malignancies such as Kaposi
sarcoma.
The major immunologic finding in AIDS is the striking decrease of T helper
cells or CD4-positive cells. Suppressor cells that have the CD8 antigen are usually
normal or slightly elevated. This results in a reversal of the normal helper-tosuppressor T cell ratio, which is about 1.9. Most individuals with AIDS have ratios
much lower than 0.9 and frequently near 0. In contrast, B cell numbers are usually
normal.
The presence of circulating antibody against the AIDS virus apparently indicates
infection by the virus. Antibody appears soon after infection through blood
products, usually within 4 or 7 weeks. After sexual exposure, the individual can be
infected yet seronegative for months. In the late stages of the disease, some
individuals become seronegative because of a deficient immune system. The
period between infection and the appearance of antibody is referred to as the
window period. Although the patient may not have antibody, he or she may be
viremic and infectious to other within 2 weeks of being infected.
Treatment for AIDS can involve restoration of immune function or prevention
of viral replication. Restoration of immune function has been attempted with bone
marrow transplants, transfusions of white blood cells from healthy donors, and the
injection of interleukin-2 or interferon. These attempts have shown little or no
success because the virus quickly infects the donor cells. Several agents have been
tried to prevent viral replication: a combination of therapy with a protease inhibitor
and a reverse transcriptase inhibitor, AZT, reduce or eliminate viral components in
the blood.
Drug therapy for AIDS is difficult because the AIDS retrovirus incorporates into
the genetic material of the host and may never be removed by antiviral therapy.
Therefore, drug administration may have to continue for the lifetime of the
individual.
The development of an effective AIDS vaccine has been slowed by several
major difficulties. The AIDS virus is genetically and antigenically variable. Thus a
vaccine created against one variant may not provide protection against another
variant. This is a real problem because as many as 30 to 40 different genetic
variants have been isolated from the same individual during the progression of the
disease. Many of these may coexist in the individual. Although AIDS individuals
have high levels of circulating antibodies against the virus, these antibodies do not
appear to be protective. The AIDS virus is transmitted from cell to cell and may
initially enter the body in an infected cell that is not susceptible to circulating
antibody. Also, HIV-infected cells tend to fuse with other cells so infection can
spread to uninfected cells without viral particles being produced.
Finally, the only good model for AIDS experimentation is the chimpanzee,
which is a protected animal species and relatively unavailable for medical research.
Thus efficacy and toxicity of possible vaccines cannot easily be evaluated.
5.1. Content of the theme. Characterize immune response. Describe
induction of immune response. Describe humoral and cell-mediated immune
response. Characterize cellular interaction in immune response. Describe the forms
of changes and disorders of immune system. Characterize immunodeficiencies;
describe examples of congenital or primary diseases. Cite causes and consequences
of acquired or secondary immune deficiencies. Describe the best known acquired
immune deficiency disorder, AIDS.
5.2. Control questions of the theme:
1. Characterize immune response.
2. Describe induction of immune response.
3. Describe humoral and cell-mediated immune response.
4. Characterize cellular interaction in immune response.
5. Describe the forms of changes and disorders of immune system.
6. Characterize immunodeficiencies; describe examples of congenital or primary
diseases.
7. Cite causes and consequences of acquired or secondary immune deficiencies.
8. Describe the best known acquired immune deficiency disorder, AIDS.
5.3. Practice Examination.
I. Circle the correct answer or answers for each question.
1. Antigenicity depends on:
A. Mass B. Foreignness C. Complexity D. Both B and C are correct E. A, B,
and C are correct.
2. When antigen contacts to its appropriate antibody:
A. Agglutination may occur B. Phagocytosis may occur
C. Antigen
neutralization may occur D. All of the above are correct E. None of the above is
correct.
3. Antibodies are produced by: A. B cells B. T cells C. Helper cells
D.Plasma cells E. Memory cells.
4. The primary immune response involves:
A. A rapid plasma cell response with peak antibody by three days
B. Macrophage production of antibodies
C. T cell production of antibodies
D. A latent period followed by peak antibody production.
5. Which cells are phagocytic?
A. B cells B. T cells C. T suppressors D. T killers Macrophages
6. When a child develops measles and acquires an immunity to subsequent
infections, the immunity is: A. Acquired D. Active C. Natural D. All of the
above are correct.
II. Matching
IIa. Match the term with its descriptor.
7. Antibody combining site
8. Cytokines
9. Monoclonal antibodies
10. Mucous membrane
11. Memory cell
A. Provides communication between macrophages and subsets of lymphocytes
B. Useful for diagnosis and treatment C. First line of defense D. Relies on the
specificity between antibody and antigen E. Secretes antibodies F. Long-term
immunity G. Produced after initial contact with an antigen H. Predominant
antibody of secondary response
IIb. Match the descriptor with the lymphocytic activity.
12. Capable of forming clones
13. Produce lymphokines
14. Helper and suppressor cells
15. Antibody formation
16. Cell-mediated response
A. T cell involvement B. B cell involvement C. Both T cell and B cell
involvement
IIc. Match the definition with its term.
17. Phagocytosis
18. Specific immunity
19. Macrophage
20. Nonspecific immunity
21. Antigen
A. Identical cells having descended from one cell B. Lymphocyte that attacks
antibodies directly
C. Ingestion and destruction D. Phagocytic, agranular
leukocyte of the immune system E. Resists a large variety of antibody production
F. Protein produced by T cells G. Exclusively thymus-dependen
Literature:
1. Gozhenko A.I., Makulkin R.F., Gurcalova I.P. at al. General and clinical
pathophysiology/ Workbook for medical students and practitioners.-Odessa, 2001.P.92-106.
2. Gozhenko A.I., Gurcalova I.P. General and clinical pathophysiology/ Study
guide for medical students and practitioners.-Odessa, 2003.- P.99-104.
3. Robbins Pathologic basis of disease.-6th ed./Ramzi S.Cotnar, Vinay Kumar,
Tucker Collins.-Philadelphia, London, Toronto, Montreal, Sydney, Tokyo.-1999.