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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. Disorder of immunocomponent

system in maintenance tissue structure and function.

of antigenic hemostasis.






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

The receiving of the skills

  1. histology

  2. biochemistry

  3. physiology

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 antigen-presenting 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, IL-1 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 homeostasis-immunization, 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 cell-mediated 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 bursal-equivalent 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 AIDS-virus (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-to-suppressor 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.

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