# Immunodeficiency

Immunodeficiency, also known as immunocompromise, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that affect the patient's immune system. Examples of these extrinsic factors include HIV infection and environmental factors, such as nutrition. Immunocompromisation may also be due to genetic diseases/flaws such as SCID.
In clinical settings, immunosuppression by some drugs, such as steroids, can either be an adverse effect or the intended purpose of the treatment. Examples of such use is in organ transplant surgery as an anti-rejection measure and in patients with an overactive immune system, as in autoimmune diseases. Some people are born with intrinsic defects in their immune system, or primary immunodeficiency.
A person who has an immunodeficiency of any kind is said to be immunocompromised. An immunocompromised individual may particularly be vulnerable to opportunistic infections, in addition to normal infections that could affect anyone. It also decreases cancer immunosurveillance, in which the immune system scans the body's cells and kills neoplastic ones. They are also more susceptible to infectious diseases owing to the reduced protection afforded by vaccines.

## Types
### By affected component

* Humoral immune deficiency (including B cell deficiency or dysfunction), with signs or symptoms depending on the cause, but generally include signs of hypogammaglobulinemia (decrease of one or more types of antibodies) with presentations including repeated mild respiratory infections, and/or agammaglobulinemia (lack of all or most antibody production) which results in frequent severe infections and is often fatal.
* T cell deficiency, often causes secondary disorders such as acquired immune deficiency syndrome (AIDS).
* Granulocyte deficiency, including decreased numbers of granulocytes (called as granulocytopenia or, if absent, agranulocytosis) such as of neutrophil granulocytes (termed neutropenia). Granulocyte deficiencies also include decreased function of individual granulocytes, such as in chronic granulomatous disease.
* Asplenia, where there is no function of the spleen
* Complement deficiency is where the function of the complement system is deficient
In reality, immunodeficiency often affects multiple components, with notable examples including severe combined immunodeficiency (which is primary) and acquired immune deficiency syndrome (which is secondary).
Comparison of immunodeficiencies by affected component :
| | Affected components | Main causes | Main pathogens of resultant infections |
| Humoral immune deficiency B cell deficiency | B cells, plasma cells or antibodies | Primary humoral Multiple myeloma Chronic lymphoid leukemia AIDS | Streptococcus pneumoniae Hemophilus influenzae Pneumocystis jirovecii Giardia intestinalis Cryptosporidium parvum |
| T cell deficiency | T cells | Marrow and other transplantation AIDS Cancer chemotherapy Lymphoma Glucocorticoid therapy | Intracellular pathogens, including Herpes simplex virus, Mycobacterium, Listeria, and intracellular fungal infections. |
| Neutropenia | Neutrophil granulocytes | Chemotherapy Bone marrow transplantation Dysfunction, such as chronic granulomatous disease | Enterobacteriaceae Oral Streptococci Pseudomonas aeruginosa Enterococcus species Candida species Aspergillus species |
| Asplenia | Spleen | Splenectomy Trauma Sickle-cell anemia | Polysaccharide encapsulated bacteria, particularly: Streptococcus pneumoniae Haemophilus influenzae Neisseria meningitidis Plasmodium species Babesia species |
| Complement deficiency | Complement system | Congenital deficiencies | Neisseria species Streptococcus pneumoniae |

### Primary or secondary

The distinction between primary versus secondary immunodeficiencies is 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.

#### Primary immunodeficiency

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 95 recognised 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. The characteristics of lacking and/or impaired antibody functions can be related to illnesses such as X-Linked Agammaglobulinemia and Common Variable Immune Deficiency

#### Secondary immunodeficiencies

Secondary immunodeficiencies, also known as acquired immunodeficiencies, can result from various immunosuppressive agents, for example, malnutrition, aging, particular medications (e.g., chemotherapy, disease-modifying antirheumatic drugs, immunosuppressive drugs after organ transplants, glucocorticoids) and environmental toxins like mercury and other heavy metals, pesticides and petrochemicals like styrene, dichlorobenzene, xylene, and ethylphenol. 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.
Various hormonal and metabolic disorders can also result in immune deficiency including anemia, hypothyroidism and hyperglycemia.
Smoking, alcoholism and drug abuse also depress immune response.
Heavy schedules of training and competition in athletes increases their risk of immune deficiencies.

## Causes

The cause of immunodeficiency varies depending on the nature of the disorder. The cause can be either genetic or acquired by malnutrition and poor sanitary conditions. Only for some genetic causes, the exact genes are known.

## Immunodeficiency and autoimmunity

There are a large number of immunodeficiency syndromes that present clinical and laboratory characteristics of autoimmunity. The decreased ability of the immune system to clear infections in these patients may be responsible for causing autoimmunity through perpetual immune system activation. One example is common variable immunodeficiency (CVID) where multiple autoimmune diseases are seen, e.g., inflammatory bowel disease, autoimmune thrombocytopenia, and autoimmune thyroid disease. Familial hemophagocytic lymphohistiocytosis, an autosomal recessive primary immunodeficiency, is another example. Low blood levels of red blood cells, white blood cells, and platelets, rashes, lymph node enlargement, and enlargement of the liver and spleen are commonly seen in these patients. Presence of multiple uncleared viral infections due to lack of perforin are thought to be responsible. In addition to chronic and/or recurrent infections many autoimmune diseases including arthritis, autoimmune hemolytic anemia, scleroderma and type 1 diabetes are also seen in X-linked agammaglobulinemia (XLA). Recurrent bacterial and fungal infections and chronic inflammation of the gut and lungs are seen in chronic granulomatous disease (CGD) as well. CGD is caused by a decreased production of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase by neutrophils. Hypomorphic RAG mutations are seen in patients with midline granulomatous disease; an autoimmune disorder that is commonly seen in patients with granulomatosis with polyangiitis and NK/T cell lymphomas. Wiskott–Aldrich syndrome (WAS) patients also present with eczema, autoimmune manifestations, recurrent bacterial infections and lymphoma. In autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) also autoimmunity and infections coexist: organ-specific autoimmune manifestations (e.g., hypoparathyroidism and adrenocortical failure) and chronic mucocutaneous candidiasis. Finally, IgA deficiency is also sometimes associated with the development of autoimmune and atopic phenomena.

## Antibody vulnerability period in children

The period following birth is critical for the development of a child's immune system. Initially, a newborn relies heavily on passive immunity transferred from the mother, primarily through the placenta and breastfeeding.
As breastfeeding frequency declines, immune protection gradually wanes, making the child more vulnerable and increasingly reliant on their developing immune system. This transitional phase, known as the "antibody vulnerability period", lasts until approximately three to four years of age, during which the child's immune system matures and becomes fully functional.
To combat pathogens, it is important for babies to develop their own specific antibodies recognizing these antigens. And these types of antibodies are known as immunoglobulins. Immunoglobulin G (IgG) is one of them.
Babies are unable to make their own IgG antibodies at birth and rely on maternal transfer of IgG via placenta during the third trimester. Other types of immunoglobulins (IgA, IgM, IgE and IgD) do not cross the placenta. It is believed that IgG is important in protecting babies against infections.
Naturally bioactive Immunoglobulin G is found in breast milk which plays a significant role in early life during the vulnerable period. The Y-shaped structure of Immunoglobulin G allows it to effectively identify and combat pathogens, providing antibody-like protection to the child.
Research indicates that maintaining adequate levels of IgG during early childhood may help mitigate the risks associated with this immune vulnerability. This supplementation can offer a protective boost, enhancing the infant's ability to fend off infections and other health threats during the critical years when their immune system is still developing. The importance of this period underscores the need for targeted nutritional interventions to support overall immune health in young children.

### Classes of immunoglobulins (Igs)

The immune system produces several classes of immunoglobulins (Ig), such as IgA, IgD, IgE, IgG, and IgM. Each class helps protect the body from infection in a different way (see below).

### Immunoglobulin Subclasses and Their Properties

Immunoglobulin Subclasses :
| Subclass | Structure | Antigen Binding Sites | Crosses Placenta | Total Antibody in Serum | Fc Binds to | Functions |
| IgM | Pentamer | 10 | No | 6% | Complement | Main antibody of primary responses, best at fixing complement. Monomer form serves as B cell receptor. |
| IgG | Monomer | 2 | Yes | 80% | Phagocytes | Main blood antibody of secondary responses, neutralize toxins, opsonization. All antibodies are Y shape, only some are dimer (sIgA) or pentamer (IgM). The Y-shaped structure has sites that effectively identify and bind pathogens. Able to suppress more than 99% of the antibody response against the bound antigen. |
| IgA | Dimer | 4 | No | 13% | None | Secreted into mucus, tears, saliva, colostrum. |
| IgE | Monomer | 2 | No | 0.002% | Mast cells and basophils | Antibody of allergy and antiparasitic activity. |
| IgD | Monomer | 2 | No | 1% | None | B-cell receptor. |

## Diagnosis

Medical History and Physical Examination: A physician will inquire about past illnesses and family history of immune disorders to identify inherited conditions. A detailed physical examination helps recognize symptoms indicative of an immune disorder. Blood Tests: these tests are instrumental in diagnosing immunodeficiency as they measure: Infection-fighting proteins (immunoglobulins): Essential for robust immune defense, these protein levels are measured to evaluate immune function. Blood cell counts: Deviations in specific blood cells can point to an immune system anomaly. Immune system cells: These assessments are used to measure the levels of various immune cells. Genetic testing involves collecting samples from patients for molecular analysis when there is a suspicion of inborn errors in immunity. Most Primary Immunodeficiency Disorders (PIDs) are inherited as single-gene defects. The key genes associated with immunodeficiency diseases include CD40L, CD40, RAG1, RAG2, IL2RG, and ADA. Here is a summary of some methods utilized to identify genetic anomalies: Sanger Sequencing of Single Genes: Sanger sequencing is widely recognized as the benchmark method for accurately identifying individual nucleotide changes, as well as small-scale insertions or deletions in DNA. It is particularly valuable for confirming known familial genetic variations, for validating findings from next-generation sequencing technologies, and in specific scenarios that require sequencing of single genes. An example is its use to confirm mutations in the Bruton tyrosine kinase (BTK) gene, which are linked to X-linked agammaglobulinemia (XLA) • Targeted Gene Sequencing Panels (tNGS): This technology is ideal for examining genes in specific pathways or for follow-up experiments (targeted resequencing) from whole genome sequencing (WGS). It is rapid and more cost-effective than WGS, and because it allows for deeper sequencing. • Whole Exome Sequencing (WES): is a commonly used method which captures the majority of coding regions of the genome for sequencing, as these regions contain the majority of disease-causing mutations Useful for identifying mutations in specific genes • Trio or Whole-Family Analyses: In some cases, analyzing the DNA of the patient, parents, and siblings (trio analysis) or the entire family (whole-family analysis) can reveal inheritance patterns and identify causative mutations

## Treatment

Available treatment falls into two modalities: treating infections and boosting the immune system.
Prevention of Pneumocystis pneumonia using trimethoprim/sulfamethoxazole is useful in those who are immunocompromised. In the early 1950s Immunoglobulin(Ig) was used by doctors to treat patients with primary immunodeficiency through intramuscular injection. Ig replacement therapy are infusions that can be either subcutaneous or intravenously administered, resulting in higher Ig levels for about three to four weeks, although this varies with each patient.

## Prognosis

Prognosis depends greatly on the nature and severity of the condition. Some deficiencies cause early mortality (before age one), others with or even without treatment are lifelong conditions that cause little mortality or morbidity. Newer stem cell transplant technologies may lead to gene based treatments of debilitating and fatal genetic immune deficiencies. Prognosis of acquired immune deficiencies depends on avoiding or treating the causative agent or condition (like AIDS).