Immunodeficiencies in Humans

In this article we will discuss about the primary and secondary immunodeficiencies seen in humans.

Primary Immunodeficiencies:

An immunodeficiency that arises from a genetic or developmental defect in the immune system is called a primary immunodeficiency. Such defects are present at birth and become manifest at different stages during development. Most defects affect either the lymphoid (giving rise to B and T-cells) or myeloid (giving rise to macrophages) cell lineages, or the complement system.

Lymphoid cell disorders may affect T-cells, B-cells or both B- and T- cells, while myeloid disorders affect phagocytic functions. Most of the primary immunodeficiencies are inherited, and their precise molecular and genetic basis are known (Table 43.3). But some immunodeficiencies arise from developmental defects that impair proper function of an organ of the immune system.

The effects of immunodeficiency depend on the component of the lymphoid and myeloid cell lineages affected. A defect in an early component would involve the entire immune system, while a defect in a later more differentiated component would affect a single function.

For example, reticular dysgenesis is caused by a stem-cell defect; this interferes with the maturation of all leucocytes resulting in a general failure of the immune system so that patients die young from severe infection. In contrast, an individual suffering from selective IgA deficiency may enjoy a normal life-span, except for a greater than normal susceptibility to infections of the respiratory and genitourinary tracts.

Lymphoid immunodeficiencies may involve B- cells, T- cells or both B- and T-cells, the last being the most serious of immunodeficiencies. A T-cell deficiency can affect both the humoral and the cell-mediated responses. Lymphoid immunodeficiencies have the common feature of the inability to mount or sustain a complete immune response against specific agents.

In addition, often a single form of immunodeficiency can arise due to different genetic defects, e.g., in the cases of severe combined immunodeficiency (SCID) and gammaglobulinemias (Table 43.3).

The treatment of primary immunodeficiencies offers the following possibilities replacement of

(1) The missing protein,

(2) Missing cell type or lineage, and

(3) The missing or defective gene.

Administration of the missing protein is the classic treatment for disorders that impair antibody production; pooled human gamma­globulin can be given either intravenously or subcutaneously in many types of immunodeficiency.

Monoclonal and hybrid antibodies, and other immunologically important recombinant proteins, e.g., IFN-γ (used in the case of chronic granulomatus disease, CGD) can used for the treatment of specific immunodeficiencies.

Cell replacement approach is based on transfer of stem cells from an immuno-competent donor into the patient; the success rate is high when the donor has HLA alleles identical to those of the patient (ideal donor). In case of non-ideal donors, the donor bone marrow cells are processed to select for CD34⁺ stem cells and to deplete T-cells in order to minimise the risk.

This therapy has been used successfully in infants with SCID. Paternal CD34⁺ cells were injected in utero in two cases where birth of infants with SCID was expected; the newborns showed normal T cell function and did not develop the infections that characterise SCID.

Secondary Immunodeficiencies:

The loss of immune function as a result of exposure to various agents, such as, human immunodeficiency virus 1 (HIV 1), is called secondary or acquired immunodeficiency. HIV infection produces acquired immunodeficiency syndrome, which has acquired epidemic proportions in certain populations and almost inevitably results in death.

AIDS patients and other individuals with severe immunodeficiency are at the risk of infection by opportunistic agents-, these agents are microorganisms that do not adversely affect healthy individuals, but that cause disease in these individuals. AIDS was first reported in U.S.A. in 1981; in 1998, a total of 33.4 million people had AIDS/HIV.

The common means of transmission of HIV include homosexual and heterosexual intercourse, transfusion of HIV-infected blood or blood products, and passage from infected mothers to their infants (~30% infants get infected unless the mothers are treated with antiviral agents before delivery).

In many cases, it may take a long period following HIV infection for the AIDS symptoms to appear; however, the HIV carrier may infect others during this latent period.

HIV-1 is a retrovirus and has an RNA genome, which integrates into the human genome as a DNA copy. HIV-2 is related to HIV-1, infects nonhuman primates and is less pathogenic in humans than is HIV-1.

HIV-1 infects T-cells that are CD4⁺; an envelope protein of HIV-1 binds to CD4 antigen, and the infection is assisted by T-cell co-receptor CXCR4. HIV-1 can infect monocytes and other cells that have CD4 on their surface. Once the RNA genome is inside the host cells, it is reverse transcribed into cDNA, which becomes integrated into the host genome as a provirus.

The integrated provirus is transcribed, and the various viral RNA messages are spliced and translated into proteins. The gag proteins of the virus are cleaved by the viral protease to generate subunits that make up the nuclear capsid and complete RNA copies of the provirus are packaged into new virus particles. These particles are released from the infected cells, and infect new CD4⁺ cells.

In general, antibodies against HIV proteins appear in the patients 3 months after infection; this is called seroconversion. But viral RNA is detectable in the serum soon after infection, while clinical symptoms indicative of AIDS generally do not appear for at least 8 years after infection; death may occur, on an average, 9-12 years after infection.

Diagnosis of AIDS includes presence of antibodies (most common detection method) or virus in blood, greatly reduced numbers of CD4⁺ T-cells (<200 cells/mm³), impaired or absent delayed-hypersensitivity reactions and the occurrence of opportunistic infections.

The decrease in CD4 T-cells is the hallmark of AIDS; the decrease in T-cells occurs, most likely, due to infection by HIV leading to death of the T-cells. HIV infected individuals often display dysfunction of the central and peripheral nervous systems; HIV does infect brain cells of the patients.

The various possible strategies for AIDS treatment are as follows:

(1) AIDS vaccine, and

(2) Drags that revert AIDS symptoms.

Drugs for AIDS may be designed to block:

(1) Reverse transcriptase,

(2) Viral protease and

(3) Integrase that play critical role in HIV-1 life cycle.

The drug should be specific to HIV-1 and should have minimum interaction with host enzymes.

At present, drugs targeted at reverse transcriptase and protease are in clinical use (Table 43.4). The first successful drugs were targeted at reverse transcriptase; the prototype of such drugs is zidovudine (AZT), which is a nucleoside analogue. Incorporation of a base analogue into a cDNA chain prevents its extension.

AZT is effective in some patients; its long-term use produces several side effects (since AZT is incorporated in human DNA as well) and mutant viruses develop in treated patients. But the non-nucleoside analogues like nevirapine inhibit the action of reverse transcriptase.

The current treatment for AIDS is a combination therapy based on, in most cases, two nucleoside analogues and one protease inhibitor; this strategy is called highly active antiretroviral therapy (HAART).

HAART has been remarkably successful in reducing viral load in blood below detection limits and, perhaps, in lowering death rates due to AIDS. But this therapy is very expensive (up to USD 15,000 per day), and even HAART produces side effects, which, in some cases, may prevent its use.