Immunity Disorders: Immunodeficiencies



Primary Immunodeficiency Diseases

Primary immunodeficiencies are disorders in which part of the body’s immune system is missing, or does not function properly.

Learning Objectives

Describe primary immunodeficiency disorders and explain what treatment options are available

Key Takeaways

Key Points

  • To be considered a primary immunodeficiency, the cause of the immune deficiency must not be secondary in nature (caused by other disease, drug treatment, or environmental exposure to toxins).
  • Most primary immunodeficiencies are genetic disorders; the majority are diagnosed in children under the age of one, although milder forms may not be recognized until adulthood.
  • The precise symptoms of a primary immunodeficiency depend on the type of defect but generally include recurrent or persistent infections or developmental delay as a result of infection.

Key Terms

  • genetic disorder: An illness caused by abnormalities in genes or chromosomes, especially a condition that is present prior to birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions.
  • immunodeficiency: A depletion in the body’s natural immune system, or in some component of it.

Primary immunodeficiencies are disorders in which a part of the body’s immune system is missing or does not function properly. To be considered a primary immunodeficiency, the cause of the immune deficiency must not be secondary in nature (caused by another disease, drug treatment, or environmental exposure to toxins). Most primary immunodeficiencies are genetic disorders; the majority are diagnosed in children under the age of one, although milder forms may not be recognized until adulthood.

Symptoms

The precise symptoms of a primary immunodeficiency depend on the type of defect. Generally, the symptoms and signs that lead to the diagnosis of an immunodeficiency include recurrent or persistent infections, or developmental delay as a result of infection. Particular organ problems; such as diseases involving the skin, heart, facial development and skeletal system; may be present in certain conditions. Others predispose to autoimmune disease, where the immune system attacks the body’s own tissues, or tumors (sometimes specific forms of cancer, such as lymphoma). The nature of the infections, as well as the additional features, may provide clues as to the exact nature of the immune defect.

Diagnostic Tests

The basic tests performed when an immunodeficiency is suspected should include a full blood count ( including accurate lymphocyte and granulocyte counts) and immunoglobulin levels. Tthe three most important types of antibodies are IgG, IgA and IgM.

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Complete Blood Count: Schematics (also called “fishbones”) of shorthand commonly used by clinicians for complete blood count. The shorthand on the right is used more often in the U.S. Hgb=Hemoglobin, WBC=White blood cells, Plt=Platelets, Hct=Hematocrit.

Other tests are performed depending on the suspected disorder:

  • Quantification of the different types of mononuclear cells in the blood (lymphocytes and monocytes): different groups of T lymphocytes (dependent on their cell surface markers, e.g. CD4+, CD8+, CD3+, TCRα and TCRγ); groups of B lymphocytes (CD19, CD20, CD21 and Immunoglobulin); natural killer cells and monocytes (CD15+); as well as activation markers (HLA-DR, CD25, CD80 ( B cells )
  • Tests for T cell function: skin tests for delayed-type hypersensitivity, cell responses to mitogens and allogeneic cells, cytokine production by cells
  • Tests for B cell function: antibodies to routine immunizations and commonly acquired infections, quantification of IgG subclasses
  • Tests for phagocyte function: reduction of nitro blue tetrazolium chloride, assays of chemotaxis, bactericidal activity

Due to the rarity of many primary immunodeficiencies, many of the above tests are highly specialized and tend to be performed in research laboratories.

Immunodeficiency Disorders

In genetic immunodeficiency disorders, both T lymphocytes and often B lymphocytes—regulators of adaptive immunity—are dysfunctional or decreased in number. The main members are various types of severe combined immunodeficiency (SCID).

In primary antibody deficiencies, one or more isotypes of immunoglobulin are decreased or don’t function properly. These proteins, generated by plasma cells, normally bind to pathogens, targeting them for destruction.

A number of syndromes, including the following, escape formal classification but are otherwise recognisable by particular clinical or immunological features:

  • Wiskott-Aldrich syndrome
  • DNA repair defects not causing isolated SCID; for example ataxia telangiectasia and ataxia-like syndrome
  • DiGeorge syndrome (when associated with thymic defects)
  • Various immuno-osseous dysplasias (abnormal development of the skeleton with immune problems);for example, cartilage-hair hypoplasia, Schimke syndrome

In certain conditions, including the following, the regulation rather than the intrinsic activity of parts of the immune system is the predominant problem:

  • Immunodeficiency with hypopigmentation or albinism; for example, Chediak-Higashi syndrome, Griscelli syndrome type two
  • Familial hemophagocytic lymphohistiocytosis; for example, perforin deficiency, MUNC13D deficiency, syntaxin 11 deficiency
  • X-linked lymphoproliferative syndrome

Phagocytes are the cells that engulf and ingest pathogens (phagocytosis), and destroy them with chemicals. Monocytes/macrophages as well as granulocytes are capable of this process. In certain conditions, either the number of phagocytes is reduced or their functional capacity is impaired. Several rare conditions are due to defects in the innate immune system, which is a basic line of defense independent of the more advanced lymphocyte-related systems. Many of these conditions are associated with skin problems.

Rather than predisposing for infections, most of the autoinflammatory disorders lead to excessive inflammation. Many manifest themselves as periodic fever syndromes. They may involve various organs directly, as well as predisposing for long-term damage by leading to amyloid deposition.

The complement system is part of the innate as well as the adaptive immune system; it is a group of circulating proteins that can bind pathogens and form a membrane attack complex. Complement deficiencies are the result of a lack of any of these proteins. They may predispose to infections but also to autoimmune conditions.

Treatment

The treatment of primary immunodeficiencies depends foremost on the nature of the abnormality. This may range from immunoglobulin replacement therapy in antibody deficiencies—in the form of intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG)—to hematopoietic stem cell transplantation for SCID and other severe immunodeficiences. SCID can now be treated with a bone marrow transplant. Reduction of exposure to pathogens may be recommended, and in many situations prophylactic antibiotics may be advised.

Secondary Immunodeficiency Diseases

Secondary immunodeficiencies refer to acquired immune system disorders.

Learning Objectives

Define immunodeficiency and list the types that occur

Key Takeaways

Key Points

  • A deficit in the immune system can lead to unusually severe or uncommon recurrent infections.
  • Secondary immune deficiencies or acquired deficiencies, more frequent than primary immune deficiencies, are problems of the immune system that are not genetic and which are caused by external factors.
  • Secondary immunodeficiency disorders can occur in, for example, malnutrition, aging, many types of cancer (such as leukemia, lymphoma, multiple myeloma), and certain chronic infections such as acquired immunodeficiency syndrome (AIDS).
  • Immunosuppression is one form of secondary immunodeficiency performed to prevent the body from rejecting an organ transplant, treating graft-versus-host disease after a bone marrow transplant, or for the treatment of auto-immune diseases, such as rheumatoid arthritis or Crohn’s disease.
  • A person who is undergoing immunosuppression or whose immune system is weak for other reasons (for example, chemotherapy, HIV, and Lupus), is said to be immunocompromised.

Key Terms

  • immunodeficiency: A depletion in the body’s natural immune system, or in some component of it.
  • immunocompromised: Having an immune system that has been impaired by disease or treatment.
  • immunosuppressive: Having the capability to suppress the immune system, capable of immunosuppression.
  • secondary infection: any infection that arises subsequent to a pre-existing infection; but especially a nosocomial infection

Immunodeficiency (or immune deficiency) is a state in which the immune system’s ability to fight infectious disease is compromised or entirely absent. Immunodeficiency may also decrease cancer immunosurveillance. Most cases of immunodeficiency are acquired (“secondary”) but some people are born with defects in their immune system, or primary immunodeficiency. Transplant patients take medications to suppress their immune system as an anti-rejection measure, as do some patients suffering from an over-active immune system. A person who has an immunodeficiency of any kind is said to be immunocompromised. An immunocompromised person may be particularly vulnerable to opportunistic infections, in addition to normal infections that could affect everyone. Distinction between primary versus secondary immunodeficiencies are based on, respectively, whether the cause originates in the immune system itself or is, in turn, due to insufficiency of a supporting component of it or an external decreasing factor of it.

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Main Symptoms of AIDS: Acquired immunodeficiency syndrome (AIDS) is defined in terms of either a CD4+ T cell count below 200 cells per µL or the occurrence of specific diseases in association with an HIV infection. In the absence of specific treatment, around half the people infected with HIV develop AIDS within 10 years. The most common initial conditions that alert to the presence of AIDS are pneumocystis pneumonia and cachexia.

Primary Immunodeficiency (PID)

A number of rare diseases feature a heightened susceptibility to infections from childhood onward. Primary Immunodeficiency is also known as “congenital immunodeficiencies. ” Many of these disorders are hereditary and are autosomal recessive or X-linked. There are over 80 recognized primary immunodeficiency syndromes; they are generally grouped by the part of the immune system that is malfunctioning, such as lymphocytes or granulocytes. The treatment of primary immunodeficiencies depends on the nature of the defect and may involve antibody infusions, long-term antibiotics, and (in some cases) stem cell transplantation.

Secondary Immunodeficiencies

Secondary immunodeficiencies, also known as acquired immunodeficiencies, can result from various immunosuppressive agents, for example, malnutrition, aging and particular medications (e.g., chemotherapy, disease-modifying antirheumatic drugs, immunosuppressive drugs after organ transplants, glucocorticoids). For medications, the term immunosuppression generally refers to both beneficial and potential adverse effects of decreasing the function of the immune system, while the term immunodeficiency generally refers solely to the adverse effect of increased risk for infection. Many specific diseases directly or indirectly cause immunosuppression. This includes many types of cancer, particularly those of the bone marrow and blood cells (leukemia, lymphoma, multiple myeloma), and certain chronic infections. Immunodeficiency is also the hallmark of acquired immunodeficiency syndrome (AIDS), caused by the human immunodeficiency virus (HIV). HIV directly infects a small number of T helper cells and also impairs other immune system responses indirectly.

Immunotherapy for Cancer

Cancer immunotherapy is the use of the body’s own immune system to reject cancer.

Learning Objectives

Describe the use of immunotherapy in cancer treatment

Key Takeaways

Key Points

  • Cancer immunotherapy can involve immunization of the patient with a cancer vaccine, administration of therapeutic antibodies as drugs, or cell-based immunotherapy.
  • Vaccines can be raised against antigens that are inappropriate either for the cell type or for its environment.
  • Adoptive cell-based immunotherapy involves isolating either allogenic or autologous immune cells, enriching them outside the body, and transfusing them back into the patient.
  • Monoclonal antibodies can be raised against unusual antigens that are presented on the surfaces of tumors.

Key Terms

  • immunotherapy: the treatment of cancer by improving the ability of the host to reject a tumor immunologically
  • allogenic: genetically distinct, but of the same species
  • autologous: derived from part of the same individual (i.e., from the recipient rather than the donor)

Cancer immunotherapy is the use of the body’s own immune system to reject cancer. The main idea is stimulating the patient’s immune system to attack the malignant tumor cells that are responsible for the disease. This can be either through immunization of the patient (e.g., by administering a cancer vaccine such as Dendreon’s Provenge), in which case the patient’s own immune system is trained to recognize tumor cells as targets to be destroyed, or through the administration of therapeutic antibodies as drugs, in which case the patient’s immune system is recruited to destroy tumor cells by the therapeutic antibodies. Cell-based immunotherapy is another major entity of cancer immunotherapy. This involves immune cells such as the natural killer cells (NK cells), lymphokine-activated killer cells (LAK cells), cytotoxic T lymphocytes (CTLs), and dendritic cells (DC). These immune cells are either activated in vivo by administering certain cytokines such as interleukins, or they are isolated, enriched, and transfused back into the patient to fight against cancer.

Since the immune system responds to the environmental factors it encounters on the basis of discrimination between self and non-self, many kinds of tumor cells that arise as a result of the onset of cancer are more or less tolerated by the patient’s own immune system since the tumor cells are essentially the patient’s own cells that are growing, dividing, and spreading without proper regulatory control. In spite of this fact, however, many kinds of tumor cells display unusual antigens that are inappropriate for either the cell type or its environment or that are only normally present during the organism ‘s development (e.g. fetal antigens). Examples of such antigens include the glycosphingolipid GD2, a disialoganglioside that is normally only expressed at a significant level on the outer surface membranes of neuronal cells, where its exposure to the immune system is limited by the blood-brain barrier.

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Structure of GD2: GD2 is a disialoganglioside expressed on tumors of neuroectodermal origin, including human neuroblastomas and melanomas, with highly restricted expression on normal tissues, principally to the cerebellum and peripheral nerves in humans. The relatively tumor-specific expression of GD2 makes it a suitable target for immunotherapy with monoclonal antibodies or with artificial T-cell receptors.

GD2 is expressed on the surfaces of a wide range of tumor cells, including neuroblastomas, medulloblastomas, astrocytomas, melanomas, small-cell lung cancer, osteosarcomas, and other soft tissue sarcomas. GD2 is thus a convenient tumor-specific target for immunotherapies.

Adoptive cell-based immunotherapy involves isolating either allogenic or autologous immune cells, enriching them outside the body, and transfusing them back to the patient. The injected immune cells are highly cytotoxic to the cancer cells and so help to fight them.

Antibodies are a key component of the adaptive immune response. They play a central role in both the recognition of foreign antigens and the stimulation of an immune response to them. It is not surprising, therefore, that many immunotherapeutic approaches involve the use of antibodies. The advent of monoclonal antibody technology has made it possible to raise antibodies against specific antigens, such as the unusual antigens that are presented on the surfaces of tumors. A number of therapeutic monoclonal antibodies have been approved for use in humans, such as alemtuzumab, an anti-CD52 humanized IgG1 monoclonal antibody indicated for the treatment of chronic lymphocytic leukemia (CLL). Radioimmunotherapy in turn involves the use of radioactively conjugated murine antibodies against cellular antigens, mostly for treatment of lymphomas.

The development and testing of second-generation immunotherapies is already under way. While antibodies targeted to disease-causing antigens can be effective under certain circumstances, in many cases their efficacy may be limited by other factors. In the case of cancer tumors, the microenvironment is immunosuppressive, allowing even those tumors that present unusual antigens to survive and flourish in spite of the immune response generated by the cancer patient against his own tumor tissue. Certain members of a group of molecules known as cytokines, such as interleukin-2, also play a key role in modulating the immune response. Cytokines have been tested in conjunction with antibodies in order to generate an even more devastating immune response against the tumor. While the therapeutic administration of such cytokines may cause systemic inflammation, resulting in serious side effects and toxicity, there is a new generation of chimeric molecules consisting of an immune-stimulatory cytokine attached to an antibody that targets a tumor. These chimeric molecules are able to generate a very effective yet localized immune response against the tumor tissue, destroying the cancer-causing cells without the unwanted side effects.

Dermatologists use new creams and injections in the management of benign and malignant skin tumors. Topical immunotherapy utilizes an immune enhancement cream (imiquimod), which is an interferon producer, causing the patient’s own killer T cells to destroy warts, actinic keratoses, basal cell carcinoma, squamous cell carcinoma, cutaneous T cell lymphoma, and superficial spreading melanoma. Injection immunotherapy uses mumps, candida, or trichophytin antigen injections to treat warts (HPV-induced tumors).