Part of the TeachMe Series

Immunodeficiency

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Original Author(s): Emilia O'Connor
Last updated: 11th May 2021
Revisions: 7

Original Author(s): Emilia O'Connor
Last updated: 11th May 2021
Revisions: 7

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Types of Immunodeficiency

Primary immunodeficiencies are rare and inherited. They present early in life with severe, frequent or opportunistic infections. They can be due to impaired production of components of the immune system or due to a defect within existing parts of the immune system.

Secondary immunodeficiencies are more common than primary. They may occur as a consequence of infection (e.g. HIV), immunosuppression (e.g. chemotherapy) or malignancy. They can also be secondary to disease states including diabetes. These factors put stress on the body and weaken the immune system. The signs and symptoms are the similar to primary immunodeficiencies, with frequent, recurrent, and unusual infections.

Next, we will consider specific immunodeficiencies according to their underlying cause.

Primary Immunodeficiencies – B cell

B cell immunodeficiencies can be due to a failure in B cell production, a failure to produce high affinity memory cells in germinal centres, or failure to produce the usual spectrum of antibodies.

They rarely cause illness until levels of maternal IgG fall at 4-6 months. It typically presents with recurrent respiratory tract infections, particularly with encapsulated pyogenic bacteria such as Streptococcus pneumoniae and Haemophilus influenza B. Examples include:

Clinical Relevance – B cell immunodeficiencies

X-linked agammaglobulinaemia

X-linked agammaglobulinaemia (XLA) is an x-linked recessive disease, characterised by a defect in the B-cell tyrosine kinase (BTK) gene. This causes dysfunction of the tyrosine kinase in B cells. leading to an inability for B cells to differentiate and mature into functional cells.  Consequently, individuals present with severe and recurrent infections, often secondary to encapsulated bacteria. This tends to present after 6 months of life when maternal immunoglobulin begins to wane.

Figure 1 – The lack of the BTK gene leads to inadequate maturation of the pre-B cell to the immature B cell

Selective IgA deficiency

The most common primary immunodeficiency is selective IgA deficiency, in which there is an isolated deficiency in immunoglobulin A. The cause is unknown, and often cases are asymptomatic. However, it can cause respiratory infections and chronic diarrhoea. Additionally, some individuals may have severe anaphylactic reactions to IgA when receiving a blood transfusion.

Hyper-IgM syndrome

Hyper-IgM syndrome is an X-linked recessive disorder caused by a defect inthe CD40 ligand. This prevents class switching, meaning B cells can’t switch the production of IgM antibodies to IgG, IgA or IgE types. It causes recurrent respiratory, gastrointestinal, and sinus infections, due to normal or elevated levels of IgM but decreased levels of IgG and IgA.

Common variable immunodeficiency

Common variable immunodeficiency is an umbrella term for antibody deficiency where the genetic cause is unknown. The hypothesis behind this disease is that there is a genetic mutation, but an infectious trigger is required for it to manifest.

B cells are of a normal phenotype, but unable to differentiate into plasma cells. This means there are low concentrations of all classes of immunoglobulin, but particularly IgG, IgA and IgM. It has a later onset than other B cell defects, typically presenting in adulthood around the age of 20-35 with recurrent, severe sinopulmonary infections.

Primary Immunodeficiencies – T Cell

T cell deficiency can be due to reduced T cell counts, or impaired activity (Figure 2). This predisposes the sufferer to severe infections by intracellular parasites, bacteria and viruses. This can present with failure to thrive and/or diarrhoea in early life.

It is also associated with mucosal infection by yeasts such as candida (the organism that causes thrush).

Figure 2 – Normal pathway of T cell maturation in the thymus

 

Clinical Relevance – T cell immunodeficiencies

DiGeorge syndrome

DiGeorge (or 22q11.2 deletion) syndrome is autosomal dominant and caused by a deletion of the q11.2 portion of chromosome 22. The clinical features can vary, but can be remembered with the CATCH-22 acroynm:

  • Cardiac abnormalities
  • Abnormal facial features
  • Thymic hypoplasia
  • Cleft palate
  • Hypocalcaemia
  • Chromosome 22 affected

As T cells usually mature in the thymus after being produced in the bone marrow, thymic hypoplasia causes a reduction in mature, functional T-cells. Most cases are partial, meaning there is only mild to moderate thymus dysfunction which is not life threatening. In complete DiGeorge syndrome, the immunodeficiency can be fatal.

Severe combined immunodeficiency

Severe combined immunodeficiency (SCID) is caused by mutations which cause the impaired development of B and T cells. It is the most severe primary immunodeficiency, presenting in early life with severe bacterial, viral and fungal infections. Infants may also present with chronic diarrhoea and failure to thrive.

The two most common causes are X-linked and autosomal recessive adenosine deaminase deficiency.

Primary Immunodeficiencies – Neutrophils

Neutrophil defects can be due to a deficiency in neutrophil counts, or an impairment of neutrophil function. Affected individuals present with severe extracellular and gram negative bacterial infections that can be fatal, as they respond very poorly to antibiotics. These patients are especially prone to skin infections and sepsis.

Clinical Relevance – Neutrophil disorders

Chronic granulomatous disease

Chronic granulomatous disease is an X-linked or autosomal recessive inherited disorder where there is defective production of reactive oxygen species due to a defective NADPH oxidase enzyme. This decreases the oxidative burst in neutrophils, which is normally used to destroy phagocytosed pathogens. This disease presents in childhood with recurrent infections and granuloma formation.

Congenital neutropenia

Congenital neutropenia is characterised by a decreased neutrophil count, causing recurrent life-threatening bacterial infections such as gingivitis, otitis media and respiratory infections. It can be inherited in an X-linked, autosomal recessive or autosomal dominant manner.

Leukocyte adhesion deficiency type 1

Leukocyte adhesion deficiency type 1 is an autosomal recessive inherited disorder causing an impairment of neutrophil function (Figure 3). An absent CD18 protein affects the margination of neutrophils, causing them to accumulate in the blood without being able to leave the bloodstream to fight infection.

It presents with recurrent bacterial infections, especially of skin and mucosa, and delayed separation of the umbilical cord.

Figure 3 – A comparison between normal adhesion (left) and LAD-1 affected neutrophils (right)

 

Primary Immunodeficiencies – Complement

Defects in each of the complement pathways have different implications for the immune system. Deficiency in the classical pathway causes a build up of immune complexes in tissues and an associated inflammatory response. This causes diseases such as systemic lupus erythematosus and an increase in infection by encapsulated bacteria. Deficiency in the alternative pathway can cause severe bacterial infections and renal disease.

C1 esterase inhibitor deficiency (hereditary angioedema) is an autosomal dominant inherited disorder which leads to sudden uncontrolled activation of complement and bradykinin pathways. This leads to recurrent spontaneous attacks of non-itchy angioedema, which can be life-threatening if affecting the airway.

Terminal complement deficiency affects the production of C5-C9 complexes. It is autosomal recessive and causes an inability to produce antigen-antibody complexes, leading to defective opsonisation and phagocytosis. There is an increased risk of infection, particularly by Neisseria meningitidis and Neisseria gonorrhoeae.

C3 deficiency causes impaired opsonisation due to reduced levels of the opsonin C3b. This results in recurrent severe childhood infections, particularly by encapsulated bacteria such as Neisseria meningitidis and Haemophilus influenzae. C3 deficiency is also associated with autoimmune diseases and type III hypersensitivity reactions.