Immunodeficiency and Immune Deficiency Diseases

Cancer immunotherapy is a rapidly advancing medical therapy that takes advantage of the immune system to contain or eliminate cancer cells. Currently, immunotherapies have been incorporated into treatment regimens for different types of cancer. Various therapeutic approaches exist, including using cytokines, vaccines, oncolytic viruses, T-cell manipulation or cellular adoptive immunotherapy, or antibodies to immune checkpoint molecules. These therapies provide new options for advanced cancers, including melanoma, renal cell carcinoma, prostate adenocarcinoma, lung cancer, urothelial carcinoma, Hodgkin lymphoma, and refractory B-cell ALL. With the immune system involved, these agents carry serious and potentially fulminant adverse effects and toxicities.

Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Chromosomal mutations occur when an abnormal number of chromosomes is inherited. Point mutations occur when a nucleotide is swapped for another nucleotide and can be missense, nonsense, or silent mutations. Frameshift mutations occur when a nucleotide is added or deleted, and expansion mutations occur when a given trinucleotide sequence is repeated along the chromosome. Genetic mutations are the basis for most inherited diseases. Common disorders caused by DNA mutations include sickle cell disease, Huntington disease, and Tay-Sachs disease.

Common variable immune deficiency (CVID), also known as humoral immunodeficiency, is a disorder of the immune system characterized by reduced serum levels of immunoglobulins G, A, and M. The underlying causes of CVID are largely unknown. Patients with this condition are prone to infections in the gastrointestinal tract and the upper and lower respiratory tracts. CVID is also associated with a higher risk of developing autoimmune disorders, granulomatous diseases, and malignancy.

X-linked agammaglobulinemia, also known as Bruton's agammaglobulinemia or Bruton's disease, is a rare, recessive genetic disorder characterized by the improper development of B cells, leading to a lack of mature B cells capable of responding to stimulation by cell-mediated immune responses or certain antigen-presenting cells. X-linked agammaglobulinemia is more likely to be found in males than females and is due to mutations in the Bruton’s tyrosine kinase gene on the X chromosome. The result of this mutation is a complete or near-complete lack of all antibodies. Presentation includes recurrent bacterial infections after the first few months of life. Management consists of IV immunoglobulins and prophylactic use of antibiotics.

Selective immunoglobulin A (IgA) deficiency is the most common type of primary immunodeficiency. The condition is a hypogammaglobulinemia characterized by a lack or reduced levels of IgA. This antibody mainly resides in the mucous membranes of the mouth, airways, and digestive tract. The exact cause is unknown. The disease is usually asymptomatic, although some patients can present with recurrent respiratory and gastrointestinal infections as well as autoimmune and malignant disorders. Diagnosis is made with a measure of exceptionally low IgA levels in the serum in the presence of normal IgG and IgM levels.

IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome is a rare congenital T-cell deficiency associated with transcription factor FOXP3 dysfunction. This factor regulates the development of a regulatory T cell line and dysfunctions usually result in autoimmunity. The condition manifests as autoimmune enteropathy, eczematous dermatitis, nail dystrophy, autoimmune endocrinopathies, and autoimmune skin conditions. The only form of management for IPEX is bone marrow transplantation.

Severe combined immunodeficiency (SCID), also called “bubble boy disease,” is a rare genetic disorder in which the development of functional B and T cells is disturbed due to several genetic mutations that result in reduced or absent immune function. It is the most severe form of primary immunodeficiency and is characterized by dysfunction in both humoral and cell-mediated immune responses. Multiple mutations can result in heterogeneous types of SCID. Patients present with severe and recurrent infections within the first months of life. Management includes IV immunoglobulins and bone marrow transplantation. If left untreated, SCID is usually fatal within the 1st year of life.

Complement component 3 (C3) deficiency is the absence, reduction, or dysfunction of complement factor C3 and its fragments, C3a and C3b. Complement factors are key components of the innate immune system. Reduced levels of C3b increase the probability of developing infections with encapsulated organisms (e.g., Pneumococcus, Haemophilus influenza, Neisseria meningitidis), especially respiratory infections, due to reduced opsonization. Individuals with C3 deficiencies are also more susceptible to type III hypersensitivity reactions because a reduced clearance of antigen-antibody C3b complexes from the circulation causes an increased risk of hypersensitivity reactions.

Hereditary angioedema (HAE), also known as C1 esterase inhibitor (C1-INH) deficiency, is an autosomal dominant disorder characterized by recurrent episodes of severe swelling (angioedema). Hereditary angioedema commonly affects the limbs, face, intestinal tract, and upper airway. Swelling in the airway can restrict breathing and lead to a life-threatening airway obstruction. Hereditary angioedema has 3 subtypes distinguished by their underlying etiologies and levels of C1 inhibitor in the blood. Management includes treatment with danazol, kallikrein inhibitors, and C1-INHs. Hereditary angioedema is self-limiting, but may be fatal if the airway becomes compromised.

The human immunodeficiency virus (HIV) is a species of Lentivirus, a genus of the family Retroviridae, which causes HIV infections and acquired immunodeficiency syndrome (AIDS). The virus has high genetic variability and is divided into 2 major types, HIV type 1 (HIV-1) and HIV type 2 (HIV-2). The human immunodeficiency virus is a single-stranded, positive-sense, enveloped RNA virus, which targets and destroys WBCs, leading to frequent opportunistic infections and, eventually, death.

Antiretroviral therapy (ART) targets the replication cycle of the human immunodeficiency virus (HIV) and is classified based on the viral enzyme or mechanism that is inhibited. The goal of therapy is to suppress viral replication to reach the outcome of undetected viral load. Currently, reverse transcriptase, protease, integrase, and entry inhibitors are used in combined ART (cART) regimens. Combination therapy (3-drug regimen) is used to prevent drug resistance and cross-resistance, which develop through genetic mutations.

Preterm labor refers to regular uterine contractions leading to cervical change prior to 37 weeks of gestation; preterm birth refers to birth prior to 37 weeks of gestation. Preterm birth may be spontaneous due to preterm labor, preterm prelabor rupture of membranes (PPROM), or cervical insufficiency. Preterm birth may also be initiated by the provider for a variety of maternal or fetal indications. Diagnosis involves assessments to detect cervical change and monitoring for regular uterine contractions. Management depends on gestational age, but typically includes administration of corticosteroids (to improve fetal lung maturity), magnesium sulfate (for fetal neuroprotection against cerebral palsy), group B streptococcus (GBS) prophylaxis, and 48 hours of tocolytics to help patients complete a full course of steroids.

Chédiak-Higashi syndrome (CHS) is an autosomal recessive disorder caused by mutations affecting a lysosomal trafficking regulator protein. This protein plays a crucial role in the inability of neutrophils to kill phagocytosed microbes. Patients with CHS exhibit recurrent pyogenic infections, easy bleeding and bruising, and neurologic manifestations. The syndrome is also associated with oculocutaneous albinism. The diagnosis is made based on analysis of the patient’s blood or bone marrow smear and genetic testing. The treatment of choice is allogeneic hematopoietic cell transplantation.

Leukocyte adhesion deficiency type 1 (LAD1) is an inherited condition in which genetic mutations result in a lack of CD18 expression on neutrophils. These mutations lead to a decrease in the ability of neutrophils to migrate from the blood vessels to the site of injury or infection on recruitment. Patients with this condition will have recurrent infections and delayed wound healing. An elevated neutrophil count may be noted on laboratory evaluation. The diagnosis is confirmed with flow cytometry demonstrating a deficiency in CD18. Hematopoietic stem cell transplantation is the treatment of choice, and it can be curative.

The hyperimmunoglobulin M (hyper-IgM) syndrome, is a group of rare inherited immunodeficiency disorders characterized by low or absent serum levels of IgA, IgG, and IgE and normal or elevated levels of IgM. Hyper-IgM syndrome is most commonly caused by X-linked mutations in the CD40 ligand gene, which results in abnormal signaling between B and T lymphocytes. Because of the pattern of inheritance, male individuals are most commonly affected. Typically, CD40 is involved in the generation of B cells with high-affinity immunoglobulin. CD40 is also involved in the maturation of T cells. The disease has a wide range of severity, ranging from opportunistic infections in early infancy to autoimmune conditions and malignancies. Management includes immunoglobulin replacement and administration of prophylactic antimicrobial agents. The only curative approach is hematopoietic cell transplantation.

The membrane attack complex (MAC), which is formed by complement proteins, plays a crucial role in the eradication of bacterial infections, especially Neisseria species and other encapsulated bacteria, by attaching to the bacterial plasma membrane and forming pores that eventually lead to cell lysis. Patients with terminal complement pathway deficiency may present with recurrent and severe neisserial infections as they are unable to synthesize MAC because of a deficiency in one of its components (e.g., late complement proteins). Treatment is antibiotics for the infection and vaccination against encapsulated bacteria.

Chronic granulomatous disease (CGD), as the name implies, is a chronic disorder that is characterized by granuloma formation. This disorder is a consequence of defective phagocytic cells that are unable to produce bactericidal superoxide because of a defect in nicotinamide adenine dinucleotide phosphate (NADPH), the oxidase responsible for the respiratory burst in phagocytic leukocytes. The diagnosis is made by testing neutrophil function for superoxide production. Patients with CGD are at increased risk of life-threatening infections with fungi and catalase-positive bacteria. Inflammatory complications such as CGD colitis are also possible. The introduction of antimicrobial prophylaxis and the use of azole antifungals has increased the overall life expectancy of these patients.

Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. There are numerous maternal adaptations to pregnancy, both anatomic and physiologic, which occur to help support the developing fetus and prepare the mother's body for ultimate delivery. Pregnancy is not a pathologic condition, but good routine prenatal care can help achieve the best outcomes for both the mother and infant. Prenatal care includes appropriate lab and ultrasound testing, anticipatory guidance, and offering solutions or advice for common pregnancy discomforts.

T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. A functional mature T cell develops from a step-by-step process creating a T-cell receptor (TCR) complex, selecting T cells with appropriate affinity to self-antigens associated with major histocompatibility molecules (positive selection), and expressing either CD4 or CD8. In this series, cells predisposed to autoimmunity undergo apoptosis (negative selection). When released from the thymus, the naive mature T cells travel to the secondary lymphoid organs for activation. Two signals, an antigen-specific binding of TCR and costimulation, are required to be activated (ready to mount an immune response). In the case of CD8+ T cells, additional cytokine stimulation is necessary. Depending on the cytokines they are exposed to during antigen stimulation, the undifferentiated mature T cell (Th0) develops into cells with different functions: CD4+ become T helper (Th) cells and CD8+ become cytotoxic, or cytolytic, cells. Th cells have other subtypes; the most characterized are Th1, Th2, Th17, follicular Th cells, and regulatory T cells. Other types include natural killer T cells and memory T cells. These mature differentiated T cells ensure effective surveillance and immediate response to pathogens, tumor cells, and foreign tissues and provide immunologic memory.

Cell-mediated immunity is an integral part of the adaptive immune system, mounting a highly specific defense against pathogens. Cell-mediated immunity develops over a longer period of time than innate immunity. Cell-mediated adaptive response occurs in cells/tissues (intracellular infections or aberrant cells (e.g., tumors)) and involves the T cells or T lymphocytes. The cells, which arise from bone marrow, migrate to the thymus for further maturation. A T cell receptor is assembled and activation is facilitated by antigen-presenting cells in secondary lymphoid organs. Influenced by cytokines, activated T cells can differentiate into subsets (e.g., CD4+ T helper cells, CD8+ cytotoxic T cells, memory T cells). T helper cells aid in the eradication of pathogens by helping the partners of immune cells (e.g., macrophages and granulocytes). With mechanisms activating the caspase pathway, cytotoxic T cells have the capacity to kill microbes. Memory T cells develop after initial exposure to the antigen and become effector T cells on reinfection. T cells also activate B cells (a major component in humoral immunity), which enhance the ability to eliminate pathogens.

DiGeorge syndrome (DGS) is a condition caused by a microdeletion at location q11.2 of chromosome 22 (thus also called 22q11.2 syndrome). There is a defective development of the third and fourth pharyngeal pouches, leading to thymic and parathyroid hypoplasia (causing T-cell immunodeficiency and hypocalcemia, respectively). Conotruncal anomalies present as congenital heart defects. Other manifestations consist of characteristic facial features, frequent infections, and neuropsychiatric disorders.

Malaria is an infectious parasitic disease affecting humans and other animals. Most commonly transmitted via the bite of an infected female Anopheles mosquito, malaria is caused by single-celled microorganisms of the Plasmodium genus. Patients present with fever, chills, myalgia, headache, and diaphoresis after a history of exposure in an area endemic to malaria, which is often cyclical. Prophylaxis is of utmost importance. Treatment with oral medications is available, but malaria can be severe and fatal without a timely diagnosis, especially in young children.

Measles (also known as rubeola) is caused by a single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae and the genus Morbillivirus. It is highly contagious and spreads only among humans by respiratory droplets or direct-contact transmission from an infected person. Typically a disease of childhood, measles classically starts with cough, coryza, and conjunctivitis, followed by a maculopapular rash. Complications include diarrhea, pneumonia, and encephalitis. Measles can be prevented through vaccination, and thanks to this, had largely been eradicated until recent years. Most cases are managed with supportive care, although in select patients, antivirals can be indicated.

Human immunodeficiency virus (HIV), a single-stranded RNA virus belonging to the Retroviridae family, is the etiologic agent of acquired immunodeficiency syndrome (AIDS). The human immunodeficiency virus is a sexually transmitted or blood-borne infection that attacks CD4+ T lymphocyte cells, macrophages, and dendritic cells, leading to eventual immunodeficiency. The presentation is marked by constitutional symptoms such as lymphadenopathy and fever. Further progression predisposes to opportunistic infections and malignancies. Diagnosis is by enzyme immunoassay for HIV-1 and -2. Additional tests include HIV viral load, genotyping, and CD4+ T lymphocyte count to determine therapy and evaluate treatment response and disease progression. Immediate treatment with combination antiretroviral therapy is recommended.

Wiskott-Aldrich syndrome (WAS), also known as eczema-thrombocytopenia-immunodeficiency syndrome, IMD2, or immunodeficiency 2, is a rare genetic mixed disorder of B- and T-cell deficiency that follows an X-linked recessive inheritance pattern. It is caused by a WAS gene mutation that leads to impaired actin cytoskeleton, phagocytosis and chemotaxis, impaired platelet development, and, in general, a loss of humoral and cellular responses. Wiskott-Aldrich syndrome presents as a classic triad of eczema, bleeding diathesis, and recurrent opportunistic infections, but also carries a high risk of development of autoimmunity and malignancy. Management includes hematopoietic stem cell transplantation (HSCT), immunoglobulin replacement therapy, prophylactic and therapeutic antibiotics, and systemic steroids. Without HSCT, prognosis is poor and life expectancy is shortened.