Secondary immunodeficiency can be defined as the occurrence of cellular or humoral immunodeficiency in an individual who had an intact immune system before the onset of the condition. These acquired forms of immunodeficiency result from a diverse number of causes which include infections, as a side effect of cytotoxic drugs, malignancy and malnutrition.

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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

The most common cause of acquired immunodeficiency in the developing world is malnutrition. Protein-calorie malnutrition is usually implicated in these cases.

Malnutrition can ensue because of deprivation of all kinds of food, marasmus, or because of protein deficiency, kwashiorkor. Patients are clearly underweight and have muscle wasting in both conditions, but generalized edema is only encountered in kwashiorkor. Usually, patients develop a mixed picture.

The thymus gland, which is implicated in the production and maintenance of T-cell immunity, is atrophic in patients with severe malnutrition. Additionally, thymic hormone production is significantly reduced in these patients.

As a consequence, T-cell mediated delayed-type hypersensitivity reaction, lymphocyte proliferation, and CD4+ differentiated T-cells are all reduced. While immunoglobulins are not affected in malnutrition-related immunodeficiency, antigen processing by B-cells is usually impaired due to the inability of antigen presentation by T-cells.

Neutrophils and other polymorphonuclear leucocytes also show impairments in malnourished patients. They show abnormal phagocytosis and inability for intracellular killing of engulfed organisms. Natural killer cells also show a decrease in function.

Malignancy and Immunodeficiency

Any form of malignancy can be associated with immunodeficiency in the end-stages of the disease. However, certain hematologic malignancies are associated with early secondary immunodeficiency and they should be studied in depth to understand the mechanisms of inducing immunodeficiency. Lymphoid malignancies are known to be 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; lymphoma, leukemia and multiple myeloma.

Lymphomas and Immunodeficiency

While immunoglobulins deficiency has been reported in advanced non-Hodgkin lymphomas, Hodgkin lymphomas are more commonly associated with impaired immunity. 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 as a consequence of impaired T-cell responses to antigens. As a result of this, patients with Hodgkin lymphoma usually show lower rates of allografts rejection.

Similar to malnutrition, immunoglobulins are not reduced in Hodgkin lymphoma. In contrast to malnutrition induced immunodeficiency, patients with Hodgkin lymphoma show normal phagocytosis and the polymorphonuclear leucocytes retain their ability for intracellular killing.

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 immunity responses due to the inability of B-cell differentiation into plasma cells. The inability to differentiate into plasma cells causes hypogammaglobulinemia. As a consequence, patients with chronic lymphocytic leukemia are unable to develop an immune response against typhoid, diphtheria, tetanus, mumps, influenza and vibrio vaccines.

Patients who have a markedly low IgG level are at 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 normal T-cell function with impaired B-cell response.

Multiple Myeloma and Immunodeficiency

Patients with multiple myeloma develop impaired immunity due to the abundance of 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 is 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 have been also associated with impaired delayed type hypersensitivity reaction and the inability of lymphocytes to process antigens for poorly understood reasons.

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

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. Epstein-Barr virus is associated with impaired T-cell responses and immunosuppression. As a consequence, patients with acute infectious mononucleosis develop an impaired delayed hypersensitivity response, and a reduction in natural killer cells 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. In the acute stage, CD8+ T-cells are increased, but later on all T-cells and B-cells subtypes are decreased. 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 cells activity and inability of antigen processing and presenting by macrophages.

Drugs and Immunodeficiency

Corticosteroids are used for their anti-inflammatory action in addition to their immunosuppressive properties. Corticosteroids affect immune responses by two different mechanisms. They impact leukocyte traffic and leukocyte functions.

Glucocorticoids decrease the number of circulating CD4+ T-cells after the first injection by sequestration of 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 affect interleukins production. IL-1, IL-2, IL-4 and IL-6 production is reduced after the administration of glucocorticoids. Corticosteroids also impact macrophages by limiting their ability to phagocyte and kill bacteria or other infecting organisms.

Cytotoxic agents induce immunodeficiency by killing immune-related precursors. They therefore have an effect on 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 have more effect on T-cells rather than on B-cells. They do not impact macrophages function 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 has an effect on 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, impaired antigen processing and presentation. Additionally, full-term neonates are also largely dependent on maternal IgA and IgG antibodies, which cross via the placenta or breast milk and have protective effects for the neonate.

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.

Aging and Immunodeficiency

Aging also affects the immune response, especially T-cells. The thymus gland decreases in size by 3% annually after puberty. As a result of this, response to infections and different vaccines decline in the elderly. Additionally, patients show impaired neutrophils, macrophages and natural killer cells activity.

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