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Inherited Immune Deficiencies

This module will help you

• understand the immune system better by looking at the impact of immune deficiencies.
• learn some of the characterized congenital immune deficiency diseases.
• test your knowledge and immunology problem-solving skills.

Congenital deficiencies in immune effector mechanisms have contributed greatly to our understanding of the immune system. For example, children born with DiGeorge's syndrome who were found to lack a thymus provided evidence that the thymus was important for immune function decades before its role in T cell development was understood. Many of these deficiencies are summarized in the table below. Some deficiencies lead to increased bacterial or viral infections that can be treated with antibiotics or administration of passive antibodies, while others eliminate adaptive immunity and are fatal within the first year of life. Since before the advent of antibiotics all immune deficiencies were fatal, mutant genes responsible for inherited deficiencies are generally recessive. Production of knock-out mice has allowed us to identify genes controlling other immune functions (see Designer Mice).

Immune deficiencies are associated with recurrent infections. A battery of tests is available for diagnosing specific immune deficiencies (see ToolBox). Routine blood tests provide information about the principal types of white blood cells; specific subtypes and presence of adhesion molecules and other cell surface proteins are quantified using flow cytometry. Phagocyte function is assessed by measuring phagocytosis, intracellular killing of bacteria, and reduction of nitro blue tetrazolium dye. Plasma proteins, including Ig isotypes and antigen-specific antibodies, are detected using immunoelectrophoresis and quantified by ELISA. T cell function is assessed by measuring antigen-stimulated proliferation, cytokine production, or cytotoxicity.

Deficiencies in innate immunity generally result in recurrent bacterial and fungal infections. Neutropenia (low numbers of circulating neutrophils) is characterized by recurrent and prolonged infections,often Staphylococcal, that have minimal clinical signs (fever, inflammation), respond poorly to antibiotics, and involve skin and mucous membranes. If respiratory burst enzymes are defective, microbes grow in phagocytes, causing multiple abscesses and giant-cell granulomas. Adhesion-molecule deficiencies lead to skin infections, gingivitis, and deep tissue abscesses. Complement deficiencies result in increased bacterial infections, especially with Neisseria species. Deficiency in C1-INH results in hereditary angioneurotic edema, while lack of complement regulatory proteins DAF and CD59 results in lysis of erythrocytes (paroxysmal nocturnal hemoglobinuria; see Complement).NK cell deficiency is associated with increases in viral infections (especially Herpes viruses).

Humoral, cellular, and combined adaptive immune deficiencies have been characterized. Bruton's X-linked agammaglobulinemia results from a failure of Btk tyrosine kinase function that blocks B cell development and antibody production. Selective deficiencies occur in the ability to produce IgA and in class switching to IgG, IgA and IgE. Antibody deficiencies are the easiest to treat, since infusion of pooled human gamma globulin from immune populations is very effective at reducing incidence of infection. Failure to express TAP proteins or Class I MHC alleles inhibits development of CD8 cells and increases susceptibility to virus infections. Failure to express Class II MHC alleles inhibits development of CD4 cells and increases susceptibility to all pathogens. DiGeorge syndrome is a failure of the thymus to develop and produce mature T cells; general immunosuppression is the result. Severe Combined Immune Deficiency (SCID) results from lack of a number of different enzymes required for lymphocyte development. Infants born with SCID die from infection in the first year of life unless they receive a successful bone marrow transplant. Mutations in Fas generally result in increased incidence of lymphoid cancers because T and B cells do not undergo Fas-mediated apoptosis.

ADA = adenosine deaminase; PNP = purine nucleotide phosphorylase; XLA = X-linked agammaglobulinemia.

Infants commonly experience a dip in serum antibodies between 3-12 months of age. Maternal IgG acquired in utero is eliminated from the baby's circulation, and infants only become able to make their own IgG at about 6 months of age. Infants during this period are more susceptible to infection, especially premature babies who are born with lower levels of maternal IgG and are slower at producing their own IgG.

Individuals who must have their spleen removed following trauma and those who have artificial joints or heart valves (or "floppy" heart valves) must also take precautions to avoid bacterial infections. The spleen is responsible for removing bacteria from the blood. Artificial body parts provide attractive sites for bacterial colonization. In both cases, antibiotics are generally given prophylactically before and after dental work or other procedures likely to induce bacteria into the circulation.

Bone marrow transplantation of normal hematopoietic stem cells is the standard therapy in infants born with severe combined immune deficiency. The bone marrow donor and recipient must share at least some MHC antigens, since the recipient's T cells will be positively selected on recipient thymus stroma and must therefore recognize the same MHC on recipient APC (see T Cell Development). Another consideration for bone marrow transplantation is that the marrow may contain mature T cells from the donor; if these T cells recognize recipient MHC as foreign, Graft-Versus-Host Disease (GVHD) will result and can kill the recipient. GVHD is overcome by deleting mature T cells from the marrow before transplantation. There is no risk of recipient rejection of marrow cells in a recipient with SCID. For more information, see Transplantation.

Somatic gene therapy has been attempted in some children with SCID Somatic gene therapy involves taking some bone marrow stem cells from the patient and introducing good copies of the defective gene. The advantages of somatic gene therapy are that GVHD is avoided, as well as the possibility of introducing latently EBV-infected B cells from the donor that can cause a fatal B cell lymphoma in an immunosuppressed recipient. Difficulties include getting enough stem cells and introducing functional genes into them. Genes introduced into more mature hematopoietic cells are not as effective, since those cells have a limited lifespan. Partially successful therapy has been done in cases of ADA deficiency, and recently successful therapy has been done on two patients with X-linked SCID.

References

Anderson, W. F. Human gene therapy. Nature 392: 25-30, 1998.

Cavazzana-Calvo, M., S. Hacein-Bey, B. G. De Saint, F. Gross, E. Yvon, P. Nusbaum, F. Selz, C. Hue, S. Certain, J. L. Casanova, P. Bousso, F. L. Deist, and A. Fischer. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 288: 669-672, 2000.

Goldsby, R. A., T. J. Kindt, and B. A. Osborne. Kuby Immunology (4th edition), W. H. Freeman and Company, New York, 2000.

Janeway, C. A., P. Travers, M. Walport, M. Schlomchik. Immunobiology (5th edition), Garland Publishing, New York, 2001.

Kohn, D. B., M. S. Hershfield, D. Carbonaro, A. Shigeoka, J. Brooks, E. M. Smogorzewska, L. W. Barsky, R. Chan, F. Burotto, G. Annett, J. A. Nolta, G. Crooks, N. Kapoor, M. Elder, D. Wara, T. Bowen, E. Madsen, F. F. Snyder, J. Bastian, L. Muul, R. M. Blaese, K. Weinberg, and R. Parkman. T lymphocytes with a normal ADA gene accumulate after transplantation of transduced autologous umbilical cord blood CD34+ cells in ADA-deficient SCID neonates. Nat. Med. 4:775-780, 1998.

Leffell, M. S., A. D. Donnenberg, and N. R. Rose. Handbook of Human Immunology, CRC Press, New York, 1997.

Onodera, M., T. Ariga, N. Kawamura, I. Kobayashi, M. Ohtsu, M. Yamada, A. Tame, H. Furuta, M. Okano, S. Matsumoto, H. Kotani, G. J. McGarrity, R. M. Blaese, and Y. Sakiyama. Successful peripheral T-lymphocyte-directed gene transfer for a patient with severe combined immune deficiency caused by adenosine deaminase deficiency. Blood 91: 30-36, 1998.

Practice Quiz

Pick the one BEST answer for each question by clicking on the letter of the correct answer.

1. Combined cellular and humoral immune deficiencies result from lack of all of the following EXCEPT

a. a thymus.
b. Class II MHC.
c. HIV infection of CD4 T cells.
d. RAG-1 or RAG-2 products.
e. TAP.

2. If Class II MHC is not expressed in the thymus, the resulting immune deficiencies would include all of the following EXCEPT reduced

a. alternative complement activation.
b. CD8 T cell-mediated cytotoxicity.
c. macrophage activation to vesicular pathogens.
d. IgG synthesis.
e. All of the above would be involved.

3. Infants are most susceptible to bacterial infection due to low circulating levels of IgG

a. in utero (before birth).
b. at 0-3 months of age.
c. at 3-12 months of age.
d. at 12-24 months of age.
e. after the age of 2 years.

4. Chronic granulomatous disease results from a failure to perform oxidative burst. This deficiency would be most likely to interfere with

a. CTL killing of viruses.
b. dendritic cell activation to become a mature APC.
c. infected cell processing of virus peptides.
d. macrophage intracellular killing of bacteria.
e. M cell uptake of mucosal antigens.

5. Bare lymphocyte syndrome due to lack of Class I MHC expression would be expected to result in an inability to

a. activate Th1 cells to promote macrophage killing of vesicular pathogens.
b. educate any T cells in the thymus.
c. make an inflammatory response to bacterial LPS.
d. produce any CD8 T cells.
e. process endogenous antigen for presentation.

6. X-linked Hyper IgM syndrome, resulting in high levels of serum IgM and low levels of serum IgG, is caused by a defect in CD40L expression. The specific immune event that would be prevented by a defective CD40L would be

a. activation of B cells by T-independent antigens.
b. failure of B cells to provide co-stimulation for Th2 activation.
c. failure of dendritic cells to provide co-stimulation for Th2 activation.
d. failure of Th2 cells to provide co-stimulation for B cell isotype switching.
e. failure of Th2 cells to provide co-stimulation for B cell proliferation.

7. DiGeorge's syndrome is characterized by the lack of a thymus. The mouse model closest to this human disease would be a

a. knock-out mouse for RAG-1 and RAG-2.
b. knock-out mouse for a thymus.
c. nude mouse.
d. recombinant mouse for CD3.
e. SCID mouse.

8. A selective IgA deficiency would be expected to result in problems with

a. bacterial infections.
b. infections following dental work due to bacteria entering the bloodstream.
c. mucosal pathogens.
d. pathogens which can survive inside macrophages.
e. viral infections.

9. Bone marrow given to an infant with SCID must

a. be irradiated to eliminate GVHD.
b. contain hematopoietic stem cells that have been transduced with corrected copies of defective genes.
c. contain mature T cells that can begin making immune responses immediately.
d. come from a donor that shares some MHC alleles with the recipient.
e. come from one of the child's parents.

10. Difficulties with somatic gene therapy arise from all of the following EXCEPT

a. GVHD caused by mature T cells in the transplanted cells.
b. inserting a gene so that it will function properly.
c. limited life span of more mature hematopoietic cells.
d. obtaining enough stem cells.
e. transducing genetic material into stem cells.

Problems

1. Name two ways in which a deficiency in each molecule below would affect immunity. For example, "No thymus" would result in lack of mature T cells (Th and Tc) in the circulation and in the secondary lymphoid organs. Increased infections with viruses and vesicular pathogens would occur, and B cells would be unable to isotype switch to IgG.

a. C_Ha immunoglobulin gene.
b. Complement C3.
c. MHC invariant chain (Ii).
d. CD3.
e. RAG-1 or RAG-2.
f. B7
g. Fas
h. Class I MHC
i. Perforin
j. Selectin

2. How could you deplete marrow of mature T cells before using it for transplantation?

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