Bruton's Agammaglobulinemia: Symptoms, Impact and Treatment

Introduction

This write up will discuss a specific type of immunodeficiency disorder that is classified under humoral immunity disorders; it is called Bruton’s agammaglobulinemia, also known as X-linked recessive agammaglobulinemia. Firstly, I will provide an overview of the immune system (specifically the adaptive immune system focusing on B lymphocytes) followed by the pathophysiology, symptoms, diagnosis and treatment of the disease in question.

The immune system  

Physical barriers like skin, cornea, and mucosa of the respiratory, GI, and GU form the first line of defence against pathogens. However, if the pathogens manage to breach these barriers, the immune system defends the body against these pathogens through other mechanisms. The immune system constitutes of the innate (natural) immune system and the adaptive (acquired) immune system.

We will not be discussing the innate immune system in much details as this case is concerned with the adaptive immune system and more specifically B lymphocytes.

• The innate immune system is non-specific and does not confer long-lasting immunity against pathogens. It consists of:

•    Innate lymphoid cells (e.g., natural killer [NK] cells).
•    Polymorphonuclear leukocytes: neutrophils, eosinophils, basophils.
•    Mononuclear cells: monocytes, macrophages, mast cells.

• Adaptive immunity is antigen-specific and allows for a stronger immune response as well as immunological memory. It consists of:

•    B lymphocytes

They are also called B cells, and they are a type of white blood cells that function in the humoral immunityby secreting antibodies.

B lymphocytes are formed in the bone marrow and continue to mature in the bone marrow; then they migrate to secondary lymphoid organs (SLOs), where they can be activated by bindnig to an antigen coming through the circulating lymph. B cells bind to antigens via B cell receptors (BCR). The activation of B cells is enhanced by the activity of CD21, a surface receptor in complex with surface proteins CD19 and CD81. (Ambrose did not have any B cell markers CD19)

There are different types of B cells:

• Plasmablast- a short-lived, proliferating antibody-secreting cell, however, their antibodies have a weaker affinity to their target antigen compared to a plasma cell.
• Plasma cell – lives longer than plasmoblasts, however, it is non-proliferating antibody-secreting cell.
• Lymphoplasmacytoid cell – a subtype of plasma cells.
• Memory B cell – circulate through the body and initiate a stronger, quicker response when they detect the antigen that had previously activated their parent B cell.
• Follicular (FO) B Cell – found mainly in the lymphoid follicles of SLOs; they secrete high-affinity antibodies during an infection.
• Regulatory B (Breg) cell – acts as an immunosuppressive B cell; it stops the expansion of pathogenic, pro-inflammatory lymphocytes.

Antibodies:

B lymphocytes produce antibodies which are specialised proteins found in the bloodstream and bodily fluids.

Each antibody has two paratopes programmed to bind to two individual epitopes of foreign antigens.

There are different types of antibodies:

•     Immunoglobulin IgG: Most abundant; accounts for most of the protective activity against infections; it immobilises antigens and tags affected cells for destruction by other members of the immune system, such as T cells.
•     Immunoglobulin IgA: Found in body secretions; it is found in the respiratory and intestinal tract as well as tears and saliva. (L.L. Probst, 2018)
•     Immunoglobulin IgM: Largest immunoglobulin; first antibody produced during the initial or primary response to antigens. It locates and kills — with the assistance of T cells — invading bacterium that might be present in the bloodstream.
•     Immunoglobulin IgD: found in low concentrations in blood; functions as one type of B cell that aids the B cell in identifying antigens.
•     Immunoglobulin IgE: Least concentrated in circulation; very specialised as a mediator of many common allergic responses and in defence of parasite infections. It induces the release of histamines to attack invading allergens. (Wikipedia, 2018a)

Structure of antibodies

Each antibody (Ig molecule) consists of four polypeptides heterodimer – two identical heavy chains and two identical light chains connected by disulfide bonds forming  a “Y” shaped molecule.

The specifity of antibodies comes from the variable region (different amino acid sequence in the tips of the “Y”). Variable region constitutes the antibody binding region of the molecule to the different antigens.

On the other hand, the constant region is responsible for determining the mechanism used to destroy antigens (whether the antibodies will be IgM, IgG, IgA, IgD, and IgE).(Arizona, 2000)

Role of antibodies (Forthal, 2014)

         Neutralisation of infectivity.

         Phagocytosis.

         Antibody-dependent cellular cytotoxicity (ADCC).

         Complement-mediated lysis of pathogens or infected cells.

• T lymphocytes:

T lymphocytes develop from liver or bone marrow stem cells and mature in the thymus. They play a significant role in cell-mediated immunity as they can recognise antigens by proteins on their surface called T-cell receptors. They also Help B cells to differentiate. They are responsible for immune responses that lead to the rejection of a transplanted organ, autoimmune diseases, some allergic reactions, and AIDS.

There are different types of T cells:

• Cytotoxic T cells (T killer): directly terminate cells containing antigens by binding to them and lysing or causing them to burst open.
• Helper T cells:precipitate the production of antibodies by B cells and also produce substances that activate other T cells.
• Regulatory T cells: (also called suppressor T cells) suppress the response of B cells and other T cells to antigens.
• Memory T-cells.
• Natural killer T cell.

Figure 3. Immune system(VirtualMedical, 2006)

Pathophysiology of the disease:

Immunodeficiency results when a part of the immune system is missing or less active than normal, resulting in recurring infections. Immunodeficiency can be divided into:

•     Acquired immunodeficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV).
•     The result from the use of immunosuppressive medication.
•     Congenital/inherited/primary immunodeficiency which results from a defect in B cells, T cells, both, or even in the innate immune system.

When the problem is with B lymphocytes being decreased or absent, this is called Bruton’s agammaglobulinemia. This will subsequently result in a reduced ability to make antibodies.

Bruton’s agammaglobulinemia is caused by mutations in the gene that encodes Bruton tyrosine kinase (BTK) on the long arm of X chromosome. Approximately one-third of the variations are at sites CGG, which encodes for arginine. It results in a defect in maturation of pre–B lymphocytes in mature B lymphocytes, and therefore the absence plasmocytes.

Since it is X-linked, it is seen mainly in males because they only have one X chromosome thus requiring one copy of the defected gene to be affected.  While females have two X chromosomes, so it is less likely for them to have two copies of the defective gene. Therefore, females are usually carriers and may pass the defective gene on to their male children.

The below pedigree explains Ambrose case in more details:

• His grandmother is alive with no serious health problems. However, she is a carrier of the defected gene. She passed the defected gene to her son and daughter (Ambrose’s mother).
• His maternal uncle, who got the defected gene passed to him, suffered from the same disease and died from pneumonia when he was two years old.
• His mother is a carrier, and she passed the defected gene to himself.
• His maternal aunt is alive and well as she did not get the defected gene from her mother and she has two healthy children.
• Ambrose has a healthy younger sister who did not get the defected gene from her mother.
• There is no significant family history of any disease on Ambrose’s father’s side.

Figure 4. Amberose’s pedigree (M Hayfron –Benjamin 2018)

Symptoms and findings

• People with this disorder are susceptible to chronic infections particularly in the throat, skin, middle ear, and lungs (this is seen in Ambrose case as we are told that he suffered repeated infections including pneumonia, otitis media, sinus infections … etc.). As a result of chronic infections, they tend to: (Dictionary, 2012)

         Be pale and thin.

         Have skin rashes.

         Have black-and-blue marks in the skin because of broken blood vessels, especially near the surface of the skin.

         Lose hair from their head.

         Have a red inflammation of the lining of the eye (conjunctivitis).

         Have a crusty appearance on the nose from persisting nasal dripping.

• Reticuloendothelial tissue and lymphoid organs (tonsils, spleen, Peyer plaques, lymph nodes) are poorly developed. (This is manifested in Ambrose case as he doesn’t have visible tonsils)
• Failure to grow.
• Joint disease, similar to juvenile rheumatoid arthritis.
• Breakdown of red blood cells (autoimmune hemolytic anaemia).
• Kidney inflammation (glomerulonephritis).
• Skin and muscle inflammation (dermatomyositis).
• Some affected children may develop cancers such as leukaemia, lymphoma, or colon cancer. (UW Medicine, 2016)

Psychosocial impact:

Stigma – isolation – depression – problems related to work prospects (low income due to reduced ability to work) – complicated relationships (e.g. marriage).

There are great support groups (social and financial) and online health communities run by super users that help with this aspect.

Diagnosis

• Not improving rapidly when given antibiotics or getting ill from usually harmless organisms, especially if the patient gets repeatedly infected are strong indicators of immunodificiency. So medical and family history is an essential part of the diagnosing process.
• When the disorder is suspected, laboratory tests are used to determine the exact nature of the immunodeficiency. Blood tests show the count of different blood cells including immune cells. It is essential to know which particular type of lymphocytes is low, so lymphocyte proliferation test can be done to determine if the lymphocytes can respond to stimuli.
• Confirmation is made by flow cytometry which determines B and T lymphocyte levels.
• Antibody levels can also be measured by electrophoresis (the movement of charged particles suspended in a liquid on various media (e.g., paper, gel, liquid) under the influence of an applied electric field). (We notice that Ambrose had insignificant levels of IgG, IgA, and IgM.)
• Specific molecular analysis by single-strand conformation polymorphism SSCP or direct DNA analysis can be used to check for Btk ribonucleic acid.
• Prenatal testing.

PS: Antibodies (immunoglobulins) have all been found in human milk; the most abundant one though is IgA. So since Ambrose mother was breastfeeding him, this has contributed in protecting him for a while and delaying the onset of the symptoms until he is eight months old.

However, even if she hadn’t been breastfeeding him, he would still have a late onset because of transplacental IgGs. IgGs can pass through the placenta to the infant so they are transmitted from the mother (passive immunity) to the child during pregnancy, and they persist until 7–9 months after birth. After which they decrease, and due to the plasmocytes absence, immunoglobulins cannot be synthesised, and thus the disease signs start to appear.

Figure 1. Antibodies level from conception throughout childhood(StackExchange, 2015)

Treatment

• Unfortunatly, there is no cure, however, treatment is aimed at controlling infections and replacing the absent or defective components.

• Periodic injections of gamma globulin IV to make up for their decreased ability to make antibodies (to maintain the IgG levels at 500–800 mg/dl). This gives the pateitn the antibodies needed to fight common invading bacteria.

Plasma pool is prepared by taking plasma from 1000 or more plasma donors and then it is fractionated into 5 Cohn fractures:

1. fibrinogen
2. pure IgG (gamma globulin)
3. beta globulins (IgA + IgM)
4. alpha globulins
5. albumin.

• If untreated, the disease can be fatal. However, if treated generally live into their 30s or 40s (often die from chronic infections, usually of the lung).

• Antibiotics can be given for frequent infections.

• Maintain a healthy diet as malnutrition can worsen immunodeficiencies.

• Avoid being near people who are ill (as much as having colds) as patients with immunodeficieny can easily acquire infections. For the same reason, pateints ought to practice good personal hygiene, especially dental care.

• People with immunodeficiency disorders also should avoid eating undercooked food because it might contain bacteria that could cause infection.

• Genetic counselling: to help patients who are affected by or at risk of genetic disorders understand and adapt to their condition and its familial implications. One of the main aims of genetic counselling is to impower patients to make informed decisions and adaptation to the risk or condition. (Wikipedia, 2018)

• Not getting live virus vaccines like vaccines for measles, mumps, rubella (MMR) and chickenpox. However, dead vaccines are fine. The reason for this is that vaccines can cause the disease that they are meant to protect against.

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