INFECTIOUS DISEASE

 

IMMUNOLOGY - CHAPTER   NINETEEN 

IMMUNODEFICIENCY 

Abdul Ghaffar, Ph.D.
Emertius Professor of Pathology, Microbiology and Immunology
University of South Carolina

TEACHING OBJECTIVES

Know the primary and secondary immunodeficiencies

Know immunodeficiencies in AIDS and other conditions

IMMUNODEFICIENCY

Immunodeficiency is the failure of the immune system to protect against disease or malignancy.

Primary Immunodeficiency is caused by genetic or developmental defects in the immune system. These defects are present at birth but may show up later on in life.

Secondary or acquired immunodeficiency is the loss of immune function as a result of exposure to disease agents, environmental factors, immunosuppression, or aging.  

Know the major primary immunodeficiencies and their features

Understand the relationship between site of lesion and resulting immunodeficiency

Know the diagnostic tests for different immunodeficiencies

Primary immunodeficiencies are inherited defects of the immune system (figure 1). These defects may be in the specific or non-specific immune mechanisms. They are classified on the basis of the site of lesion in the developmental or differentiation pathway of the immune system.

Individuals with immunodeficiencies are susceptible to a variety of infections and the type of infection depends on the nature of immunodeficiency (Table 1).

There are variety of immunodeficiencies which result from defects in stem cell differentiation and may involve T-cells, B-cells, and/or immunoglobulins of different classes and subclasses (Table 2).

A defect in the early hematopoiesis which involves stem cells results in reticular dysgenesis that leads to general immune defects and subsequent susceptibility to infections. This condition is often fatal but very rare. It can be treated successfully by bone marrow transplantation.

Lymphoid lineage immunodeficiency
If the lymphoid progenitor cells are defective, then both the T and B cell lineages are affected and result in the severe combined immunodeficiency (SCID).  Infants suffer from recurrent infections especially by opportunistic microrganisms (bacterial, viral, mycotic and protozoan infections).

In about 50% of SCID patients, the immunodeficiency is x-linked whereas in the other half the deficiency is autosomal. Both are characterized by an absence of T cell and B cell immunity and absence (or very low numbers) of circulating T and B lymphocytes. Thymic shadows are absent on X-rays.

The x-linked severe SCID is due to a defect in the gamma-chain of IL-2 also shared by IL-4, -7, -11 and 15, all of which are involved in lymphocyte proliferation and/or differentiation. The autosomal SCIDs arise primarily from defects in adenosine deaminase (ADA) or purine nucleoside phosphorylase (PNP) genes which results is accumulation of dATP or dGTP, respectively, and cause toxicity to lymphoid stem cells.

Other genetic defects leading to SCID include those for RAG1, RAG2 and IL-7-alpha. If suspected of SCID, the patient must not receive live vaccine, as it will result in progressing disease.

Diagnosis is based on enumeration of T and B cells and immunoglobulin measurement. Severe combined immunodeficiency can be treated with a bone marrow transplant (see MHC and transplantation). Recently, autosomal SCID patients with ADA deficiency have been treated with a retroviral vector transfected with the gene with some success.

SCID includes several disorders

Recombinase activating genes
Patients having both T and B cell deficiency lack recombinase activating genes (RAG1 and 2) that are responsible for the T cell receptor and immunoglobulin gene rearrangements. These patients are athymic and are diagnosed by examining the T cell receptor (TCR) gene rearrangement. Defects in B cells are not observed in early infant life because of passive antibodies obtained from the mother. NK cells are normal in these patients. This is an autosomal recessive trait.

CD3 chain
In some SCID patients, T cells may be present but functionally defective because of deficiency in signaling mediated by the CD3 chain that is associated with the TCR.

Interleukin-2 receptor
Interleukin-2 receptor common gamma chain (IL-2Rγc) may be lacking in patients thereby preventing signaling by IL-2 and other cytokines which act as growth factors. This leads to a defect in the proliferation of T cells, B cells and NK cells. This is an autosomal recessive trait.

Adenosine deaminase
Adenosine deaminase (ADA) is an enzyme responsible for converting adenosine to inosine. ADA deficiency leads to accumulation of adenosine which results in the production of toxic metabolites that interfere with DNA synthesis. The patients have defects in T, B and NK cells.

SCIDs are autosomal recessive traits and can be treated by gene therapy or stem cell transplantation.

T cell disorders affect both cell-mediated and humoral immunity making the patient susceptible to viral, protozoal and fungal infections. Viral infections such as those by cytomegalovirus and attenuated measles in the vaccine can be fatal in these patients.

DiGeorge's Syndrome (Deletion 22 Syndrome)
This the most clearly defined T-cell immunodeficiency and is also known as congenital thymic aplasia/hypoplasia, or immunodeficiency with hypoparathyroidism. The syndrome is associated with hypoparathyroidism, congenital heart disease, low set notched ears and fish shaped mouth. These defects results from abnormal development of the fetus (3rd and 4th pharyngeal pouch) during the 6th to 10th week of gestation when parathyroid, thymus, lips, ears and aortic arch are being formed. No genetic predisposition is clear and not all DiGeorge syndrome babies have thymic aplasia. A thymic graft taken from an early fetus (13 - 14 weeks of gestation) can be used for treatment. Older grafts may result in GVH reaction. In severely immunodeficient DiGeorge patients, live vaccines may cause progressive infections.

DiGeorge syndrome is autosomal dominant (figure 2) and is caused by a deletion in chromosome 22 (figure 3). The deletions are of variable size but size does not correlate with severity of disease. In about 6% of cases, the chromosome 22 microdeletion is inherited but most cases result from de novo deletion which may be caused by environmental factors. Patients may be treated with a thymic graft.

CASE PRESENTATION

Pediatric Pathology
DiGeorge Syndrome
A 24-day-old Term Infant with Seizures
(Department of Pathology, University of Pittsburgh)

Figure 3
Deletion of genes in DiGeorge syndrome can be visualized by a fluorescent signal on only one of the two copies of chromosome 22
David Ian Wilson, University of Newcastle on Tyne - NIH

Ataxia-telangiectasia
Ataxia-telangiectasia is a deficiency of T cells associated with a lack of coordination of movement (ataxis) and dilation of small blood vessels of the facial area (telangiectasis). T-cells and their functions are reduced to various degrees. B cell numbers and IgM concentrations are normal to low. IgG is often reduced and IgA is considerably reduced (in 70% of the cases). There is a high incidence of malignancy, particularly leukemias, in these patients. The defects arise from a breakage in chromosome 14 at the site of TCR and immuinoglobulin heavy chain genes.

Wiskott-Aldrich syndrome
Wiskott-Aldrich syndrome syndrome is associated with normal T cell numbers with reduced functions, which get progressively worse. IgM concentrations are reduced but IgG levels are normal. Both IgA and IgE levels are elevated. Boys with this syndrome develop severe eczema, petechia (due to platelet defect and thrombocytopenia). They respond poorly to polysaccharide antigens and are prone to pyogenic infection.  Wiskott-Aldrich syndrome is an X-linked disorder (figure 4) due to defect in a cytoskeletal glycoprotein, CD43.

MHC deficiency (Bare leukocyte syndrome)
A number of cases of immunodeficiency have been described in which there is a defect in the MHC class II transactivator (CIITA) protein gene, which results in a lack of class II MHC molecules on their APC. Since the positive selection of CD4 cells in the thymus depends on the presence of these MHC molecules, these patients have fewer CD4 cells and are infection prone. There are also individuals who have a defect in their transport associated protein (TAP) gene and hence do not express the class I MHC molecules and consequently are deficient in CD8⁺ T cells.

There are a number of diseases in which T cell numbers and functions are normal: B cell numbers may be low or normal but immunoglobulin levels are low.

X-linked infantile hypogammaglobulinemia
X-linked hypogammaglobulinemia, also referred to as Bruton's hypoglobulinemia or agammaglobulinemia, is the most severe hypogammaglobulinemia in which B cell numbers and all immunoglobulin levels are very low. The patients have failure of B-cell maturation associated with a defective B cell tyrosine kinase (btk) gene. Thus, B cells exist as pre-B cells with H chains but not L chains rearranged. Diagnosis is based on enumeration of B cells and immunoglobulin measurement. Patients have no immunoglobulins and suffer from recurrent bacterial infections.

Transient hypogammaglobulinemia
Children, at birth, have IgG levels comparable to that of the mother. Because the half life of IgG is about 30 days, its level gradually declines, but by three months of age normal infants begin to synthesize their own IgG. In some infants, however, IgG synthesis may not begin until they are 2 to 3 years old. This delay has been attributed to poor T cell help. This results in a transient deficiency of IgG which can be treated with gamma-globulin.

Common variable hypogammaglobulinemia (Late onset hypogammaglobulinemia)
These individuals have deficiencies of IgG and IgA in the 2nd or 3rd decade of their life because B cells fail to differentiate into plasma cells. These patients are susceptible to a variety of pyogenic bacteria and intestinal protozoa. They should be treated with specially prepared gamma-globulin for intravenous use.  

IgA deficiency
IgA deficiency is the commonest of all immunodeficiencies (1/700 of all Caucasians) and results from a defect in class switching. About 20% of individuals with IgA deficiency also have low IgG. IgA-deficient patients are very susceptible to gastrointestinal, eye and nasopharyngeal infections. Patients with IgA deficiency have a high incidence of autoimmune diseases (particularly immune complex type) and lymphoid malignancies. Anti-IgA antibodies (IgG) are detected in 30 to 40 percent of patients who should not be treated with γ-globulins. Laboratory diagnosis is based on IgA measurement.

Selective IgG deficiency
Deficiencies of different IgG subclasses have been found. These patients are susceptible to pyogenic infections. 

X-linked Hyper-IgM immunodeficiency
Individuals with this type of immunodeficiency have low IgA and IgG concentrations with abnormally high levels of IgM. These patients cannot make a switch from IgM to other classes which is attributed to a defect in CD40L on their CD4 cells. They are very susceptible to pyogenic infection and should be treated with intravenous gamma-globulins.

Primary immunodeficiencies of the non-specific immune system include defects in phagocytic and NK cells and the complement system.

Congenital Agranulomatosis
Patients have a decrease in the neutrophil count. This is due to a defect in the myeloid progenitor cell differentiation into neutrophils. These patients are treated with granulocyte-macrophage colony stimulating factor (GM-CSF) or G-CSF.

Defects of the phagocytic system
Defects of phagocytic cells (numbers and/or functions) can lead to increased susceptibility to a variety of infections.

Cyclic neutropenia
This is marked by low numbers of circulating neutrophil approximately every three weeks. The neutropenia lasts about a week during which the patients are susceptible to infection. The defect appears to be due to poor regulation of neutrophil production.

Chronic granulomatous disease (CGD)
CGD is characterized by marked lymphadenopathy, hepato- splenomegaly and chronic draining lymph nodes. Leukocytes have poor intracellular killing (figure 5) and low respiratory burst. In majority of these patients, the deficiency is due to a defect in NADPH oxidase (cytochrome b₅₅₈ : gp91^phox, or rarely gp22^phox) or other cofactor proteins (gp47^phox, gp67^phox) that participate in phagocytic respiratory burst. These patients can be diagnosed on the basis of poor Nitroblue tetrazolium (NBT) reduction which is a measure of respiratory burst. Interferon-gamma therapy has been successful.

Leukocyte Adhesion Deficiency
In this disease, T cells and macrophages lack the complement receptor CR3 due to a defect in CD11 or CD18 peptides and consequently they cannot respond to C3b opsonin. Alternatively there may a defect in integrin molecules, LFA-1 or mac-1 arising from defective CD11a or CD11b peptides, respectively. These molecules are involved in diapedesis and hence defective neutrophils cannot respond effectively to chemotactic signals. Treatment is with bone marrow (devoid of T cells and MHC-matched) transplantation or gene therapy.

Chediak-Higashi syndrome
Chediak-Higashi syndrome is marked by reduced (slower rate) intracellular killing and chemotactic movement accompanied by inability of phagosome and lysosome fusion and proteinase deficiency. Giant lysosomes (intracellular granules) are often seen (figure 6). The respiratory burst is normal.  Accompanying NK cell defects and platelet and neurological disorders are noted.

Complement abnormalities also lead to increased susceptibility to infections. There are genetic deficiencies of various components of complement system, the most serious of which is the C3 deficiency which may arise from low C3 synthesis or deficiency in factor I or factor H. 

SECONDARY (ACQUIRED) IMMUNODEFICIENCIES 

Immunodeficiencies associated with infections
Bacterial, viral, protozoan, helminthic and fungal infections may lead to B cell, T cell, PMN and macrophage deficiencies. Most prominent among these is acquired immunodeficiency syndrome (AIDS). Secondary immunodeficiencies are also seen in malignancies.

Immunologic abnormalities in the AIDS
All acquired immunodeficiencies have been outdone by AIDS that is caused by Human Immunodeficiency Virus (HIV)-1. This virus was first discovered in 1981 and the patients exhibited fungal infections with opportunistic organisms such as Pneumocystis carinii and in other cases, with a skin tumor known as Kaposi's sarcoma. There are two major types of HIV: HIV-1 and 2, the former being the strain frequently found in North America. HIV is spread through sexual intercourse, infected blood and body fluids as well as  from mother to offspring. HIV is a retrovirus with RNA that is reverse transcribed to DNA by reverse transciptase (RT) following entry into the cell. The DNA is integrated into the cell genome as a provirus that is replicated along with the cell. HIV-1 does not replicate in most other animals but infects chimpanzees although it does not induce AIDS in them. Severe combined immunodeficient mice (SCID) reconstituted with human lymphocytes can be infected with HIV-1. The HIV-1 virion consists of a viral envelope made up of the outer lipid bilayer of the host cell in which are embedded glycoproteins composed of the transmembrane gp41 along with the associated gp120. The gp120 binds the CD4 expressed on host cells. Within the viral envelope is the viral core or nucleocapsid consisting of a layer of matrix protein composed of p17 and an inner capsid made up of p24. The viral genome consists of two single stranded RNA molecules associated with two RT molecules as well as other enzymes including a protease and an integrase.

Replication cycle and targets of therapy
The virus attaches to the CD4 molecule on Th cells, monocytes and dendritic cells through the gp120 of HIV. For HIV infection, a co-receptor is required. The co-receptor is a chemokine receptor such as CXCR4 or CCR5. CCR5, expressed predominantly on macrophages, and CXCR4 on CD4+ T cells serve as coreceptors for HIV infection. After the fusion of HIV envelope and the host membrane, the nucleocapsid enters the cell. The RT synthesizes viral DNA which is transported to the nucleus where it integrates with the cell DNA in the form of a provirus. The provirus can remain latent until the cell is activated when the provirus also undergoes transcription. Virions, consisting of the transcribed viral RNA and proteins, are produced. These bud out of the host cell membrane from where they acquire the envelope. Thus, therapeutic agents have been developed that target viral entry and fusion, as well as serve as RT, protease and integrase inhibitors. Highly active anti-retroviral therapy is a cocktail of 3 or more such agents.

Immunological Changes
The virus replicates rapidly and within about two weeks the patient may develop fever. The viral load in the blood increases significantly and peaks in two months, after which there is a sudden decline because of the latent virus found in germinal centers of the lymph nodes. CTL develop very early whereas antibodies can be detected between 3 - 8 weeks. The CTL killing of Th cells around 4 - 8 weeks leads to a decrease in CD4+ T cells. When the CD4+ T cell count decreases below 200 per cubic mm, full blown AIDS develops.

Immunotherapy
There are several barriers to development of an effective HIV vaccine.

• Attenuated vaccine may induce the disease

• CD4+ T cells may be destroyed by the vaccine

• Antigenic variation of HIV

• Low immunogenicity of the virus by downregulation of MHC molecules

• Lack of animal models

• Lack of in vitro tests

The following reagents have been considered in developing vaccines

• Immunization with deletion mutants to reduce pathogenicity

• Vaccination with recombinant proteins

• Gene encoding proteins introduced into virus vectors may be used for vaccination

• Chemokines that compete for the co-receptors

• IL-2 to boost the Th cells.

For more on HIV and AIDS go here

 

Immunodeficiencies associated with aging
 These include a progressive decrease in thymic cortex, hypo-cellularity of and reduction in the size of thymus, a decrease in suppressor cell function and hence an increase in auto-reactivity, a decrease in CD4 cells functions. By contrast B cells functions may be somewhat elevated.

Immunodeficiencies associated with malignancies and other diseases
B cell deficiencies have been noted in multiple myeloma, Waldenstrom's macroglobulinemia, chronic lymphocytic leukemia and well differentiated lymphomas. Hodgkin's disease and advanced solid tumors are associated with impaired T-cell functions. Most chemotherapeutic agents used for treatment of malignancies are also immunosuppressive.

Other conditions in which secondary immunodeficiencies occur are sickle cell anemia, diabetes mellitus, protein calorie malnutrition, burns, alcoholic cirrhosis, rheumatoid arthritis, renal malfunction, etc.

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