Immunodeficiency�Disorders

• When the system fails to protect the host from disease causing agents, the result is immunodeficiency

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• Immunodeficiency resulting from an inherited genetic or developmental defect in the immune system is called a primary immunodeficiency.

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• Secondary immunodeficiency, also known as�acquired immunodeficiency, is the loss of immune function that results from exposure to an external agent, often an infection.

Primary Immunodeficiencies

• To date, over 150 different types of primary, or inherited, immunodeficiency have been identified.
• These diseases can be caused by defects�in virtually any gene involved in
• immune development or function,
• innate or adaptive,
• humoral or cell mediated,
• genes not previously associated with immunity
• Most of these disorders are monogenic

Severe Combined Immunodeficiency (SCID)

1. Defective cytokine signaling in T-cell precursors, caused by mutations in certain cytokines, cytokine receptors, or regulatory molecules that control their expression

�2. Premature death of the lymphoid lineage due to accumulation of toxic metabolites, caused by defects in the purine metabolism pathways

�3. Defective V(D)J rearrangement in developing lymphocytes, caused by mutations in the genes for RAG1 and RAG2, or other proteins involved in the rearrangement process

�4. Disruptions in pre-TCR or TCR signaling during development, caused by mutations in tyrosine kinases, adapter molecules, downstream messengers, or transcription factors involved in TCR signaling

• Adenosine deaminase (ADA) deficiency

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• Adenosine deaminase catalyzes conversion of adenosine or deoxyadenosine to inosine or deoxyinosine,

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• intracellular accumulation of toxic adenosine metabolites, which interferes with purine metabolism and DNA synthesis.

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• these toxic compounds also produce neurologic and metabolic symptoms, including deafness, behavioral problems, and liver damage.

• In reticular dysgenesis (RD),
• the initial stages of hematopoietic cell development are blocked by defects in the adenylate kinase 2 gene (AK2),
• favoring apoptosis of myeloid and lymphoid precursors and resulting in severe reductions in circulating leukocytes

bare-lymphocyte syndrome

• A failure to express MHC molecules can lead to general failures of immunity
• Without class II MHC molecules, positive selection of CD4 T cells in the thymus is impaired,
• Defect in class II MHC gene promoter �

DiGeorge syndrome

• failure of the thymus to undergo normal development
• results from various deletions in a region on�chromosome 22
• All populations of T cells, including helper, cytolytic, and regulatory varieties, are affected.
• symptoms of immunodeficiency, hypoparathyroidism, and congenital heart anomalies �

Wiskott-Aldrich Syndrome (WAS)

• a cytoskeletal protein, WAS protein (WASP), is expressed in hematopoietic cells
• required for assembly and reorganization of actin filaments in cells of the hematopoietic lineage,
• lower than normal levels of IgM, as well as�impaired cell-mediated immunity , eczema and thrombocytopenia
• recurrent bacterial infections, especially by encapsulated strains �

Hyper IgM Syndrome (HIM)

• An inherited deficiency in CD40 ligand
• leads to impaired communication between T cells and antigen-presenting cells
• recurrent infections, especially in the respiratory tract. �

Hyper IgE Syndrome (Job Syndrome)

• multisystem disorder
• mutation in the STAT3 gene
• important for TH17 cell differentiation
• characterized by skin abscesses, recurrent pneumonia, eczema, and
• elevated levels of IgE,
• accompanied by facial abnormalities and bone fragility.

X-linked agammaglobulinemia (X-LA), or Bruton’s hypogammaglobulinemia

• defect in Bruton’s tyrosine kinase (Btk),
• which is required for signal transduction through the BCR
• B-cell development in the bone marrow is�arrested
• characterized by extremely low IgG levels
• absence of other immunoglobulin classes
• suffer from recurrent bacterial infections

Selective IgA Deficiency

• The defect in IgA deficiency is related to the inability of IgA expressing B cells to undergo normal differentiation to the plasma-cell stage
• infections of the respiratory and genitourinary tracts
• intestinal malabsorption, allergic disease,�and autoimmune disorders � �

Common Variable Immunodeficiency Disorders

• reduction in the levels of one or more antibody isotype (hypogammaglobulinemia) �and impaired B-cell responses to antigen,
• Respiratory tract infection by common bacterial strains is the most common symptom
• recurrent infection resulting from immunodeficiency �

Leukocyte Adhesion Deficiency

Chronic Granulomatous Disease

• impacts phagocytic function
• two distinct forms: an X-linked form in and an autosomal recessive form
• Defect in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidative pathway
• phagocytes generate superoxide radicals and other reactive compounds that kill phagocytosed pathogens

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• CGD patients suffer from infection by bacterial and fungal pathogens
• excessive inflammatory responses that lead to the formation of granulomas
• defective phagosome oxidase (phox) proteins that participate in this pathway �

Chediak-Higashi Syndrome

• autosomal recessive disease is an example of a lysosomal storage and transport disorder
• characterized by recurrent bacterial infections
• defects in blood clotting, pigmentation and neurologic function.
• neutropenia (depressed numbers of neutrophils) a well as impairments in T cells, NK cells, and granulocytes
• with oculocutaneous albinism, or light colored skin, hair, and eyes, accompanied by photosensitivity.

• The underlying cause is mutations in the lysosomal trafficking regulator (LYST) gene
• that cause defects in the LYST protein,
• important for transport of proteins into lysosomes as well as for controlling lysosome�size, movement, and function.
• results in enlarged organelles and defective transport functions.

• Affected phagocytes produce giant granules, and unable to kill engulfed pathogens,
• melanocytes fail to transport melanin
• enlarged lysosome-like structures in platelets and nerve cells are also thought to interfere with blood clotting and neurologic function

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Complement Deficiencies

Complement Deficiencies

Treatment options for immunodeficiencies include the following:

• Use of antimicrobial agents,
• Replacement of a missing protein
• Replacement of a missing cell type or lineage
• Replacement of a missing or defective gene �

Secondary Immunodeficiencies

• AIDS resulting from HIV infection
• drug treatment,
• metabolic disease, or
• malnutrition ��

Retrovirus HIV-1 Is the Causative�Agent of AIDS

Genetic organization of HIV-1

HIV Infection of Target Cells and Activation of Provirus

HIV Infection of Target Cells and Activation of Provirus

Stages in the viral replication cycle that provide�targets for therapeutic antiretroviral drugs.

Why AIDS does not fit the paradigm for classic vaccine development

• Classic vaccines mimic natural immunity against reinfection generally seen in individuals recovered from infection; there are no recovered AIDS patients.
• Most vaccines protect against disease, not against infection; HIV infection may remain latent for long periods before causing AIDS.
• Most vaccines protect for years against viruses that change very little over time; HIV-1 mutates at a rapid rate and efficiently selects mutant forms that evade immunity.
• Most effective vaccines are whole-killed or live-attenuated organisms; killed HIV-1 does not retain antigenicity and the use of a live retrovirus vaccine raises safety issues.
• Most vaccines protect against infections that are infrequently encountered; HIV may be encountered daily by individuals at high risk.
• Most vaccines protect against infections through mucosal surfaces of the respiratory or gastrointestinal tract; the great majority of HIV�infection is through the genital tract.
• Most vaccines are tested for safety and efficacy in an animal model before trials with human volunteers; there is no suitable animal model for HIV/AIDS at present.

Cancer and the Immune System

• Cells that give rise to clones of cells that can expand in an uncontrolled manner will produce a tumor or neoplasm
• A tumor that is not capable of indefinite growth and does not invade the healthy surrounding tissue extensively is said to be benign.
• A tumor that continues to grow and becomes progressively more invasive is called malignant;
• uncontrolled growth, malignant tumors exhibit metastasis, whereby small clusters of cancerous cells dislodge from the original tumor, invade the blood or lymphatic vessels, and are carried to other distant tissues, where they take up residence and continue to proliferate.

Types of cancers

• carcinomas, tumors that arise from epithelial origins such as skin, gut, or the epithelial lining of internal organs and glands. Skin cancers and the majority of cancers of the colon, breast, prostate, and lung are carcinomas.
• the leukemias, lymphomas, and myelomas�are malignant tumors of hematopoietic cells derived from the bone marrow. Leukemias proliferate as single detached cells, whereas lymphomas and myelomas tend to grow as tumor masses.
• Sarcomas, derived from mesodermal connective tissues, such as bone, fat, and cartilage

Tumor Antigens