Immunodeficiencies

Question 1

Give examples of primary immunodeficiencies (e.g. involving primarily lymphocytes; combined immunodeficiencies; involving phagocytic cells)

Answer 1

Primary immunodeficiencies are disorders in which, part of the immune system is missing or does not function normally

1) Immunodeficiencies Primarily Affecting Lymphocytes:

• X-linked Agammaglobulinemia (XLA): The body produces very few B cells, leading to low levels of antibodies. Resulting in frequent bacterial infections as the body has a reduced ability to fight them
• DiGeorge Syndrome (22q11.2 Deletion Syndrome): The thymus gland is underdeveloped, leading to reduced T cells, affecting the body’s ability to fight off viral and fungal infections, also can impact the body’s ability to regulate the immune response

2) Combined Immunodeficiencies (Both T cells and B cells Affected):

• Severe Combined Immunodeficiency (SCID): T cell and B cell immunity are compromised or absent, ‘bubble boy’ where mild infections lead to severe reactions
• Wiskott-Aldrich Syndrome (WAS): Caused by mutations in the WAS gene resulting in fewer immune cells, also affecting the immune system’s ability to form blood clots. Fewer and smaller platelets (microthrombocytopenia), recurrent infections due to dysfunction of the immune system and eczema

3) Immunodeficiencies Involving Phagocytic Cells:

• Chronic Granulomatous Disease (CGD): This is a disorder of phagocytes, where it is unable to destroy certain types of bacteria and fungi, leading to recurrent infections, and the formation of granulomas (clusters of immune cells that form at sites of infection or inflammation)
• Leukocyte Adhesion Deficiency (LAD): In LAD, phagocytes lack certain proteins needed for them to move to the site of infection, adhere to other cells, and destroy pathogens, resulting in recurrent bacterial and fungal infections and delayed wound healing

Question 2

Describe the main mechanisms, symptoms, and laboratory investigations for various primary immunodeficiencies

Answer 2

1) X-linked agammaglobulinemia (XLA):

• Mechanism: XLA is caused by a mutation in the BTK gene which is necessary for B-cell development, leading to a near-complete lack of B cells and consequently immunoglobulins
• Symptoms: Recurrent bacterial infections, particularly of the ears, lungs and GI tract. They also have an increased susceptibility to enteroviral infections leading to meningitis
• Lab investigations: Diagnosis involves measuring serum Ig levels which will be significantly low or absent, flow cytometry can be used to analyse B cell numbers which will be significantly low or absent

2) Severe combined immunodeficiency (SCID):

• Mechanism: SCID involves multiple genetic mutations leading to severe impairment or absence of both humoral (B cells) and cellular (T cells) immunity
• Symptoms: Severe recurrent infections, failure to thrive, chronic diarrhoea and severe thrush
• Lab investigations: Complete blood count may show lymphopenia, quantitative Ig will be low or absent. Confirmatory testing involves flow cytometry to identify T cell, B cell and NK cell numbers as well as their function

3) Chronic Granulomatous Disease (CGD):

• Mechanism: Defect in the NADPH oxidase complex, which phagocytes use to generate reactive oxygen species (ROS) to kill ingested microbes
• Symptoms: Recurrent bacterial and fungal infections, granuloma formation and inflammation in various parts of the body
• Lab investigations: Dihydrorhodamine (DHR) flow cytometry, which measures the ability of neutrophils to produce ROS

4) DiGeorge Syndrome (DGS):

• Mechanism: Deletion of a small piece of chromosome 22, resulting in poor development of the thymus and parathyroids, impacting T cell production and function
• Symptoms: Heart defects, poor immune system function, a cleft palate, complications related to low levels of calcium in the blood
• Lab Investigations: Fluorescence in situ hybridisation (FISH) test is used to identify the microdeletion in chromosome 22. Low T cell numbers can also be detected via flow cytometry

5) Wiskott-Aldrich Syndrome (WAS):

• Mechanism: A rare X-linked recessive disease characterised by eczema, thrombocytopenia (low platelet count) and immune deficiency. Caused by a mutation in the WAS gene; impacts the ability of immune cells to respond appropriately to foreign invaders
• Symptoms: Increased risk for autoimmune diseases and malignancies
• Lab Investigations: Microthrombocytes on a peripheral blood smear, low platelet count and immunodeficiency seen as low IgM and IgG with normal or elevated IgA and IgE

Question 3

Describe the main principles of treatment for various immunodeficiencies

Answer 3

1) Replacement of missing components:

• Applicable to primarily to humoral immunodeficiencies, where the missing or non-functional components are antibodies
• Immunoglobulin replacement therapy, IVIG (intravenous immunoglobulin) can be administered, obtained from healthy human donors.
• Offers passive immunity

2) Stimulation of Immune Function:

• In some Severe combined immunodeficiencies (SCID), bone marrow transplant or hematopoietic stem cell transplantation (HSCT) can be performed.
• The donated stem cells can give rise to a new immune system
• Additionally, gene therapy may be used to introduce functional genes into the person’s own stem cell in some SCID variants

3) Prevention of Infections:

• Prophylactic antibiotics are used to prevent infections
• Vaccination is also an essential part of prevention, but it must be dead or inactive pathogens

4) Treatment of Underlying Cause:

• When the immunodeficiency is secondary, e.g. HIV, antiretroviral therapy (ART) is used to reduce the viral load and slow the progression of the disease

Question 4

Describe AIDS as an example of secondary immunodeficiencies

Answer 4

Acquired Immunodeficiency Syndrome (AIDS) is an example of a secondary immunodeficiency caused by the Human Immunodeficiency Virus (HIV)

Unlike primary immunodeficiencies, which are usually caused by genetic defects, secondary immunodeficiencies like AIDS occur due to external factors, such as infection, malnutrition, aging, or medical treatments

HIV virus targets CD4+ T cells, required to initiate responses to infections

HIV binds to the CD4 receptor and another co-receptor (CCR5 or CXCR4) on the T cell surface and then integrates into the host cell genome

Once inside, the virus uses the cell’s machinery to replicate and eventually burst out, killing the cell

As HIV infection progresses, the number of CD4+ T cells gradually declines, leading to a weakened immune system; susceptible to opportunistic infections and cancers that a healthy immune system would ordinarily resist

The diagnosis of AIDS is made when the CD4+ T cell count falls below 200 cells per microlitre or when one or more opportunistic infections develop

Lab investigations for HIV include HIV antibody tests, p24 antigen tests, and viral RNA tests

Treatment for AIDS involves the use of antiretroviral therapy (ART), which aims to reduce the viral load, prevent HIV progression, and prevent HIV transmission

Prophylactic treatment against opportunistic infections is also a crucial aspect of managing patients with AIDS. For example, patients with low CD4 counts may be given prophylactic antibiotics to prevent Pneumocystis pneumonia