Topic 19 Immunodeficiency disease

Introduction

In this lesson we will learn about some of the diseases that result from defects in the immune system. Immune deficiency disorders can roughly be divided into those disorders with a deficiency or malfunction of one or more of the major aspects of the immune response, namely: B-cell or antibody mediated immunity, T-cell-mediated immunity, both B and T cell-mediated immunity, immunity mediated by the action of the phagocytic cells, and immunity associated with the activation of serum complement. This classification, however imperfect, provides a manageable way of dealing with the broad spectrum of immune disorders. Any defect in the immune system that reduces the ability of an individual to mount either cell-mediated or antibody-mediated immune responses or interferes with the ability of phagocytic cells to ingest and destroy bacteria or process antigen results in infection. These defects are of two general types. Some defects are inherited as a result of a mutation in the parents’ genes. Thus they have no obvious predisposing cause and are called primary immunodeficiencies. Because they are inherited, their effects are seen in infants and young children. The second major type of defect in the immune system is one caused by a known agent such as a drug or virus that destroys lymphocytes. This type of immunodeficiency is called a secondary immunodeficiency (or acquired immunodeficiency). Secondary immunodeficiencies commonly occur in adults or in the aged.

Objectives

On completion of this section and the required readings, you should be able to:

n construct a table comparing four different Phagocytic deficiency diseases;

n construct a table comparing 4 different humoral deficiencies;

n X linked agammaglobulinemia

n X-linked hyper IgM (XHM) syndrome

n Common variable hypogammaglobulinemia(CVH)

n Selective IgA Deficiency;

n draw a diagram of hematopoiesis and indicate congenital defects that impair the immune response for the following:

n phagocytic deficiencies,

n humoral deficiencies

n cell mediated deficiencies

n combined immunodeficiencies;

n discuss the impact of T cell deficiencies;

n construct a table of the combined immunodeficiencies that shows the disease, the immune system deficiency and the possible mechanism;

n discuss the use of CB-17 SCID mice as a model system.

Required Reading

Please refer to the Textbook Key for specific readings for this lesson.

P Key Words

• immunodeficiency • agranulocytosis (granulocytopenia, neutropenia) • congenital agranulocytosis, • leukocyte-adhesion deficiency • lazy leukocyte syndrome • chronic granulomatous disease (CGD) • X linked agammaglobulinemia • X-linked hyper IgM (XHM) syndrome • common variable hypogammaglobulinemia (CVH)

• selective Iga Deficiency • DiGeorge Syndrome (Congential thymic aplasia) • nude mice • reticular dysgenesis • bare lymphocyte syndrome • severe combined immunodeficiency disease (SCID) • X linked SCID • Wiskott-Aldrich syndrome (WAS)

P Key Concepts

n Immune deficiency disorders are called primary when the deficiency is the cause of a disease and secondary when the deficiency is a result of other diseases or the effects of treatment regiments.

n Immune deficiency diseases may be due to disorders in the development or function of B cells, T cells, phagocytic cells, or components of complement.

n As a general rule, individuals who fail to develop a functional T-cell system will die from viral infections. Individuals who fail to develop a B-cell system will die from bacterial infections.

n Inherited deficiencies in the immune system vary in severity according to the precise site of the lesion. Thus individuals who fail to develop any functioning immune system whatsoever are much more severely affected than individuals who fail to produce a single immunoglobulin class.

DID YOU KNOW?

ADA Gene Therapy

The enzyme adenosine deaminase (ADA) normally converts deoxyadenosine to deoxyinosine. In the absence of ADA, deoxyadonosine phosphate accumulates within cells. This compound is toxic for both helper and effector T cells and so causes a combined immunodeficiency. Although ADA deficiency is a rare disease, it has been the prime candidate for gene therapy for several reasons. The disease itself results from the accumulation of toxic adenine metabolites. As a result, it is not necessary to replace the enzyme in every cell of the body. It is sufficient that enough enzyme be provided to ensure that the toxin metabolites are removed. ADA can be simply provided by a blood transfusion. The ADA in the transfused red cells will, for a period, remove the adenine metabolites and permit a temporary return to normal. However, the transfused red cells last only a few weeks, and thus repeated transfusions are necessary for a significant therapeutic benefit. Purified ADA is also of significant benefit but cannot provide a cure.

To provide a lasting cure, gene therapy has been used. The gene for ADA was first inserted into a retrovirus vector. Long-lived stem cells were taken from the patient’s bone marrow and cultured. Next, the genetically engineered virus was mixed with the stem cells, and they gained the ability to make the missing enzyme. Finally, the altered stem cells were transfused back into the patient in the hope that they would continue to make the enzyme and prevent the accumulation of toxic immunosupressive metabolites.

The first recipients of this gene therapy were two young girls aged 11 and 6. They had both suffered from one severe infection after another. Respiratory infections succeeded each other with distressing regularity, and their conditions gradually deteriorated as progressive tissue damage occurred. Once their problem was identified as an ADA deficiency, they were treated with a modified bovine ADA. Within a few months their clinical condition improved as the infections stopped. The treatment saved their lives but clearly did not cure them, and it had a few adverse side effects. Gene therapy was therefore decided on. In late 1990 and early 1991, the girls received their own bone marrow cells that had been infected with retroviral vector containing the ADA gene. The treated cells were simply injected intravenously. These initial injections, although successful, could not provide permanent cures since the transfused cells lived only for a few months and the transfusion had to be repeated. However, since there were no significant side effects, it was decided to use engineered stem cells. The stem cells could replenish themselves and thus provide a permanent cure. Following this treatment, the girls appear to be permanently cured.

Tizard Immunology, an Introduction

Review Questions

1. Textbook Study Questions

Review questions at the end of the Chapter 21. The answers with explanations are available at the end of the textbook.

2. Multiple Choice Questions

1. An 8-month-old baby has a history of repeated gram-positive bacterial infections. The most probable cause for this condition is that:

A) the mother did not confer sufficient immunity upon the baby in utero

B) the baby suffers from erythroblastosis fetalis

C) the baby has a defect in the alternative complement pathway

D) the baby is allergic to the mother’s milk

E) non of the above

2. Which of the following immune deficiency disorders is associated exclusively with an abnormality of the humoral immune response:

A) X-linked agammaglobulinemia

B) DiGeorge syndrome

C) Wiskott-Aldrich syndrome

D) chronic mucocutaneous candidiasis

E) hereditary angioneurotic edema

3. The failure of the thymus to develop is called

A) reticular dysgenesis

B) combined immunodeficiency

C) secondary immunodeficiency

D) Wiskott-Aldrich syndrome

E) DiGeorge anomaly

4. In old age, which component of the immune system appears to be most impaired:

A) B cells

B) neutrophils

C) NK cells

D) macrophages

E) T cells

3. Definitions/Short Answer Questions

1. How does immunodeficiency differ from immunotolerance?

2. List the possible causes of the immunodeficiency disease

3. What would be the predicted clinical signs of a deficiency in thymic hormones?

4. Bone marrow transplantation is a common treatment for many immunodeficiency diseases. What are the advantages and disadvantages of this form of therapy?

5. List the most common clinical consequence(s) of C3 deficiency .