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HIV-infected H9 T-cell

Image: “HIV-infected H9 T-cell.” by National Institutes of Health (NIH). License: Public Domain


Malnutrition and Immunodeficiency

Malnutrition is the most common cause of acquired immunodeficiency in the developing world, and protein-calorie malnutrition is usually implicated in these cases.

There are two types of protein-calorie malnutrition:  Marasmus and kwashiorkor. Marasmus is caused by a deficiency of protein and other nutrients; kwashiorkor is caused by protein deficiency. Patients with either condition are clearly underweight and have muscle wasting, but generalized edema occurs only in kwashiorkor.

Pathogenesis 

The thymus gland, which is implicated in producing and maintaining T-cell immunity, is atrophic in patients with severe malnutrition. These patients also have significantly reduced thymic hormone production. Therefore, T-cell mediated delayed-type hypersensitivity reactionlymphocyte proliferation, and CD4+ differentiated T-cells are also reduced. While immunoglobulins are not affected in malnutrition-related immunodeficiency, the ability of B-cells to process antigen is usually impaired because the T-cells cannot present antigen.

Malnourished patients also have impaired neutrophils and other polymorphonuclear leucocytes. They show abnormal phagocytosis  (inability for intracellular killing of engulfed organisms). Natural killer cells do not function as effectively.

Malignancy and Immunodeficiency

Any form of malignancy can be associated with immunodeficiency in the end-stages of the disease. However, certain hematologic malignancies, such as hemolytic anemia, leucopenia, or thrombocytopenia, are associated with early secondary immunodeficiency. Thus, they should be studied in-depth to understand the mechanisms of inducing immunodeficiency.

Lymphoid malignancies are associated with acquired immunodeficiency and an increased risk of infections.

We will focus on three main types of lymphoid malignancies that are clearly associated with an increased risk of immunodeficiency:

Lymphomas and Immunodeficiency

While immunoglobulin deficiency has been reported in advanced non-Hodgkin lymphomas, Hodgkin lymphomas are associated with impaired immunity more often. Hodgkin lymphoma can cause T-cell deficiency, depletion of T-cell precursors in lymphoid tissues, and lymphopenia.

Additionally, patients with Hodgkin lymphoma show impaired delayed-type hypersensitivity reactions because of impaired T-cell responses to antigens. Thus, patients with Hodgkin lymphoma usually have lower allograft rejection rates.

Immunoglobulins are not reduced in Hodgkin lymphoma, similar to malnutrition. However, patients with Hodgkin lymphoma show normal phagocytosis, and the polymorphonuclear leucocytes retain their ability for intracellular killing, unlike patients with malnutrition-induced immunodeficiency.

Non-Hodgkin lymphoma induces impaired immunity due to the continuous depletion of B cells and T cells.

Leukemia and Immunodeficiency

Patients with leukemia do not develop impaired T-cell or B-cell immune responses except for chronic lymphocytic leukemia.

Patients with chronic lymphocytic leukemia develop impaired B-cell immune responses due to the  inability of B-cells to differentiate into plasma cells, which causes hypogammaglobulinemia. Therefore, patients with chronic lymphocytic leukemia are unable to develop an immune response against typhoid, diphtheria, tetanus, mumps, influenza, and cholera vaccines.

Patients who have markedly low IgG levels are at the highest risk of developing life-threatening infections. Intravenous immunoglobulin treatment is indicated in these patients to lower the risk of acquiring infections. Patients with chronic lymphocytic leukemia have a normal T-cell function with an impaired B-cell response.

Multiple Myeloma and Immunodeficiency

Patients with multiple myeloma develop impaired immunity because of abundant abnormal immunoglobulins. Monoclonal immunoglobulins in multiple myeloma are correlated with hypogammaglobulinemia. In addition to impaired humoral immunity, patients with multiple myeloma also have impaired antigen recognition and processing by B-cells. T-cell responses are usually intact in patients with multiple myeloma.

Infections and Immunodeficiency

Bacterial infections, such as Mycobacterium leprae, which causes leprosy, are associated with impaired T-cell immune responses. Patients might develop increased T-cell activity with low levels of Mycobacterium leprae-specific antibodies, or decreased T-cell activity with very high levels of antibodies against the bacterium.

Fungal infections, such as candidiasis and histoplasmosis, are also associated with an impaired delayed-type hypersensitivity reaction as well as an inability of lymphocytes to process antigens for poorly understood reasons.

Protozoal infections, especially malaria, are associated with impaired B-cell function secondary to impaired T-cell function. Such patients have a poor response to protein-based vaccines, such as tetanus and mumps vaccines.

The measles virus is associated with impaired T-cell and B-cell function, in addition to lymphopenia. The virus can also impair the function of natural killer cells. The Epstein-Barr virus is associated with impaired T-cell responses and immunosuppression; as a result, patients with acute infectious mononucleosis develop an impaired delayed hypersensitivity response and reduced natural killer cell activity.

Cytomegalovirus infects macrophages, which in turn play an important role in immunosuppression. Infected macrophages are rendered unable to present processed antigens for recognition by T-cells and B-cells.

Human Immunodeficiency Virus

Patients with HIV infection develop lymphopenia. The acute stage is marked by an increase in CD8+ T-cells with progressive depletion of all T-cell and B-cell subtypes in later stages. CD4+ T-cells are usually more depleted than CD8+ T-cells, hence the CD4+/CD8+ ratio is usually lower than normal.

B-cells also show a wide myriad of abnormalities, which include poor response to new antigens, impaired antibody specific responses, and polyclonal hyperimmunoglobulinemia. HIV also causes impaired natural killer cell activity and an inability of macrophages to process and present antigens.

Thus, the above-stated events mark acquired immunodeficiency because of the HIV virus.

Drugs and Immunodeficiency

Corticosteroids are used for their anti-inflammatory action and their immunosuppressive properties. Corticosteroids affect immune responses because of their effects on leukocyte traffic and leukocyte functions. Corticosteroids also affect macrophages by limiting their ability to phagocyte and kill bacteria or other infecting organisms.

Glucocorticoids decrease the number of circulating CD4+ T-cells after the first injection by sequestering T-cells into the lymphoid compartments. If no further injections are administered, the total CD4+ T-cells number should return to normal in two days.

In addition to their effect on T-cells function and traffic, glucocorticoids also reduce interleukin production (IL-1, IL-2, IL-4, and IL-6).

  • Cytotoxic agents induce immunodeficiency by killing immune-related precursors. Therefore, they affect all types of immune cells, including T-cells, B-cells, and macrophages.
  • Azathioprine and its active metabolite, 6-mercaptopurine, inhibit DNA synthesis and arrest cells in the S-phase. They affect T-cells more than B-cells, but they do not impact macrophage functions or numbers.
  • Cyclophosphamide, another cytotoxic agent, inhibits DNA replication, and it is toxic to cells regardless of their cellular stage in the proliferation cycle. Cyclophosphamide is more toxic to B-cells but also affects T-cells.
  • Other drugs, such as cyclosporine and anti-T cell monoclonal antibodies, have been used in organ transplantation and are known to affect T-cell responses.

Premature Delivery and Immunodeficiency

Neonates who are delivered prematurely show impaired T-cell and B-cell responses, as well as impaired antigen processing and presentation, due to lack of exposure to maternal immunoglobulins through the placenta inside the uterus. Additionally, full-term neonates depend heavily on maternal IgA and IgG antibodies, which cross via the placenta, or breast milk, which provides immunity to neonates against infections after birth.

Pregnancy and Immunodeficiency

Pregnancy is a natural phenomenon that is associated with physiologic immunosuppression. Immunosuppression is specific to the maternal-fetal interface in the placenta. Pregnant women are at an increased risk of developing infections due to their impaired immunity.

Serum Immunoglobulins in the Newborn

“Serum Immunoglobulins in the Newborn” Image created by Lecturio

Aging and Immunodeficiency

Aging also affects the immune response, especially T-cells. The thymus gland decreases in size by 3% annually after puberty until middle age, and then by 1% annually. Therefore, the elderly’s responses to different vaccines decline. Additionally, patients show impaired neutrophil, macrophage, and natural killer cell activity, leading to immune deficiency.

Aging and Immunodefiency

“Aging and Immunodeficiency” Image created by Lecturio

In infancy, the thymus produces T-cells with a mixture of specificities.

 

T-cell numbers in the peripheral pool are maintained by the replication of circulating cells.

 

In early adult life, the thymus produces fewer T-cells.

 

In adult life, proliferation in the periphery maintains the size of the T-cell pool.

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