Immune deficiency: White blood cell that help keep your body healthy do not work as they should or don’t function at all. As a result, your immune system can attack itself and make you ill. This can cause frequent infections, rheumatoid arthritis, vasculitis, anemia, leukemia or lymphoma.

Problems with bleeding (micro-thrombocytopenia): Your blood is not able to clot as it should, or stop excessive bleeding. This happens because you have fewer and smaller blood cells that are responsible for clotting which is the platelets. It can cause bruising, nosebleeds, bloody diarrhea, bleeding under the surface of your skin and a skin rash with tiny red dots (petechiae).

Infants with loss of function Wiskott-Aldrich syndrome may present with:

• Eczema

• Immune deficiency

• Severe thrush

• Pneumonia

What causes immunodeficiency?

Primary immunodeficiency disorders are most commonly caused by inherited gene mutations. Secondary immunodeficiency disorders can be caused by a variety of things, including chronic conditions (like diabetes or cancer), drugs, radiation therapy (which is rare), long-term hospitalization, insufficient nutrition.

References:

Immunodeficiency Disorders: Symptoms, Types, and More (healthline.com)

Firstly, there is bone marrow transplantation which involves replacing the patient’s faulty bone marrow with healthy bone marrow from a compatible donor and includes pre-transplant conditioning (chemotherapy or radiation) to prepare the patient’s body and to make space for the new stem cells. Successful transplantation can restore normal blood cell production and immune function. However, it carries risks such as graft-versus-host disease (GVHD), infections, and other complications.

Secondly, there is Immunoglobulin therapy, it involves intravenous immunoglobulin (IVIG) infusions provide antibodies that help fight infections. This therapy is typically used to support patients with immune deficiency to boost the immune system and help prevent infections.

Lastly, there is platelet transfusions which involves platelet transfusions that help temporarily increase platelet levels and reduce bleeding risk, but they do not address the underlying cause of the low platelet count.

References:

Wiskott-Aldrich Syndrome (nih.gov)

Wiskott-Aldrich Syndrome - StatPearls - NCBI Bookshelf (nih.gov)

The innate immune system, our body's first line of defense against pathogens, is substantially affected in WAS patients.

Natural Killer (NK) Cells

Natural killer cells in WAS patients exhibit impaired function due to defective immunological synapse formation. The immunological synapse is a specialized cell-cell junction between an immune cell and a target cell, crucial for NK cell-mediated cytotoxicity. In WAS, the inability to properly form this synapse significantly hampers the NK cells' ability to recognize and eliminate infected or malignant cells.

Invariant Natural Killer T (iNKT) Cells

Perhaps one of the most striking effects of WAS on innate immunity is the complete absence of invariant natural killer T cells in affected individuals. These cells play a vital role in bridging innate and adaptive immunity and are important in regulating immune responses. Their absence contributes to the complex immunodeficiency observed in WAS patients.

Neutrophils

Neutrophils, the most abundant type of white blood cells, also show functional deficits in WAS. These cells display abnormal migration and motility, which can impair their ability to reach sites of infection and effectively combat pathogens. This defect is attributed to the role of WASp in regulating actin polymerization, which is crucial for cell movement.

Effects on Adaptive Immunity

The adaptive immune system, responsible for targeted and memory responses to specific pathogens, is also significantly impacted in WAS.

T Cells

T cell function is markedly compromised in WAS patients. The abnormal cytoskeleton reorganization in these cells leads to impaired adhesion and interaction with other immune cells. This affects various T cell functions, including activation, proliferation, and cytokine production. Moreover, the formation of the immunological synapse between T cells and antigen-presenting cells is disrupted, further compromising T cell-mediated immunity.

B Cells

B cell homeostasis is severely affected in WAS. There is a selective depletion of circulating mature B cells and splenic marginal zone B cells. This depletion is thought to result from increased apoptosis and decreased survival of these cells. The marginal zone B cells are particularly important for rapid antibody responses to blood-borne pathogens, and their loss contributes to the increased susceptibility to infections seen in WAS patients.

Antibody Production

Antibody responses in WAS patients are abnormal, with IgM deficiency being particularly common. This deficiency affects the ability to mount effective responses against encapsulated bacteria. Additionally, patients often show poor responses to polysaccharide antigens and may have difficulty maintaining long-term antibody responses, indicating problems with immunological memory.

References:

https://www.ncbi.nlm.nih.gov/books/NBK539838/

https://emedicine.medscape.com/article/137015-overview?form=fpf

https://radiopaedia.org/articles/wiskott-aldrich-syndrome-2

https://www.msdmanuals.com/en-sg/professional/immunology-allergic-disorders/immunodeficiency-disorders/wiskott-aldrich-syndrome

https://medlineplus.gov/genetics/condition/wiskott-aldrich-syndrome/

Wiskott-Aldrich Syndrome Protein (WASP):

• WAS is caused by mutations occurring in the WASP gene, which is the gene responsible for coding the WASP protein. WASP is crucial for the regulation of actin cytoskeleton-dependent cellular processes as well as processes uncoupled with actin polymerization like nuclear transcription programs.

• WASP is important for the function and activation of immune cells like T cells and B cells in the immune system as intact cytoskeleton network is required for many of the cellular processes that they go through, like migration, adhesion and signal transduction.

• Hence the absence or dysfunction of WASP impairs cell signaling and movement, affecting the overall immune response.

T-cell:

• Defective T-cell responses caused by the mutations of WASP affects the recognition and response to pathogens, regulation of immune responses, and the assistance in the activation of other immune cells. to opportunistic pathogens and certain viruses and bacteria.

• Dysfunction of T-cells leads to an increased vulnerability to infections, especially

B-cell:

• Defective B-cell responses caused by the mutations of WASP affects normal antibody production and responses to antigens.

• Dysfunction of B-cells leads to an increased vulnerability to infections. The body is also not able to mount effective antibody defenses.

Platelet:

• Thrombocytopenia is a symptom of WAS, and it is a condition in which a patient has low platelet counts.

• Platelets play a crucial role in immune response. They are involved in hemostasis, helping with blood clotting and wound healing. They also interact with immune cells, influencing their cell activation and function.

• Thrombocytopenia leads to bleeding disorders and increased susceptibility to infections due to a compromised immune system.

The combined dysfunction of immune components involved in the Wiskott-Aldrich Syndrome can lead to inefficient pathogen clearance, leading to recurrent and more severe infections.

References:

https://www.sciencedirect.com/topics/neuroscience/wiskott-aldrich-syndrome-protein

https://pubmed.ncbi.nlm.nih.gov/31047647/#:~:text=WASp%20functions%20in%20immune%20defense,polymerization%20like%20nuclear%20transcription%20programs.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3327460/

https://www.mayoclinic.org/diseases-conditions/thrombocytopenia/symptoms-causes/syc-20378293#:~:text=Thrombocytopenia%20is%20a%20condition%20in,plugs%20in%20blood%20vessel%20injuries.

https://www.childrenshospital.org/conditions/wiskott-aldrich-syndrome#:~:text=Because%20the%20B%20cells%20of,with%20a%20weakened%20immune%20system.