Bare Lymphocyte Syndrome and the future of treatment using stem cell therapies
by Wideacademy - Updated 14 September, 2018
- Gene Therapy
What is Bare Lymphocyte Syndrome?
Bare Lymphocyte Syndrome is a rare, severe combined immunodeficiency disease (SCID). People with the condition suffer from frequent and severe bacterial, viral or fungal infections which can result in complications or may even be fatal.
Bare Lymphocyte Syndrome is a deficiency in a part of the immune system that helps the body identity and fight infections, called major histocompatibility complex (MHC) class I and class II proteins.
Severe combined immunodeficiency diseases are a group of primary immunodeficiencies, each with its own specific genetic cause, that manifest with similar symptoms. Common features of SCID are immune system malfunction and a defective antibody response. In all cases of SCID, specialised white blood cells, called lymphocytes, are missing or function abnormally.
Lymphocytes are specialised white blood cells that protect the body by making antibodies or by attacking infected cells directly. In people with SCID common ailments and infections are life-threatening.
Bare Lymphocyte Syndrome is classified into two groups:
BLS type I, also known as HLA class I deficiency, which is very rare. There are only 30 cases reported in medical literature. People with BLS are not affected by viral infections, only bacterial.
BLS type II, which is also called MHC class II deficiency. It is more common and more severe than type I, resulting in virtually no immune protection from bacteria, viruses or fungal infections.
Signs and Symptoms
Symptoms of Bare Lymphocyte Syndrome usually start to appear in babyhood and, sometimes, in later childhood. They include:
- recurrent bacterial infections of the respiratory tract, which can lead to bronchiectasis
- ulcers on skin, face and limbs and other skin infections
- chronic diarrhoea
- recurrent and serious bacterial, viral and fungal infections that can be life-threatening. These usually appear in the respiratory, gastrointestinal and urinary tracts
- malabsorption issues
- slow physical development
- organ failure
Diagnosis is made through blood tests.
How is it treated?
Treatment for Bare Lymphocyte Syndrome is either preventative or curative.
Preventative treatment involves treating infections that arise as a result of the disorder, using antibiotics and intravenous immunoglobulin therapy, to replace the missing antibodies. Live vaccines should be avoided.
Curative treatment involves restoring normal immune system function. A bone marrow transplant or stem cell transplant is the standard curative treatment for some forms of SCID and can be used to treat Bare Lymphocyte Syndrome. It may be recommended in severe cases, such as when lung failure is present. A lung transplant might also be required.
If successful, a bone marrow transplant works very well. However, it must be from an HLA-matched sibling donor. Without a donor, the treatment becomes higher risk, with potential complications such as Graft-versus-Host Disease (GvHD). This means that many patients are not eligible for a stem cell transplant.
An autologous stem cell transplant, using gene modified haemopoietic stem cells from the patient’s own bone marrow, is an alternative approach. This could enable patients without an HLA matched donor to have the procedure.
Bare Lymphocyte Syndrome II in particular has the potential to be cured with gene therapy. However, this is still an investigational therapy and more research is needed before it can be available therapeutically.
How can stem cells help?
Haemopoietic stem cell transplants currently offer the only standard, long-term cure for severe combined immunodeficiencies such as Bare Lymphocyte Syndrome. If successful, a transplant can restore the faulty immune system, thereby enabling the bone marrow to produce healthy white blood cells.
Stem cell transplants are major operations and usually require highly toxic chemotherapy preparative regimes and a compatible donor, which can be difficult to find. They also come with the risk of serious complications such as transplant rejection and GvHD.
Advances in diagnostic techniques and genetic technology, preparative chemotherapy treatments and better medications mean the success rates of stem cell transplants are improving and are increasingly available to patients with this disease.
Whereas previously patients with SCID were more than likely to die, now they will most likely survive, and patients with successful transplants can go on to achieve long-term immune recovery.
The Masonic Cancer Center is currently investigating the best approach to treating primary immune deficiencies, such as Bare Lymphocyte Syndrome, with haemopoietic stem cell transplants. The trial is looking at different preparatory regimes; myeloablative, reduced intensity and no preparatory regimes.
Another trial led by Paul Szabolcs at the University of Pittsburgh, is testing reduced intensity conditioning regimes with different types of stem cell transplant, to see which combination achieves the best on-going graft success, for patients with non malignant diseases, such as Bare Lymphocyte Syndrome.
Reduced intensity conditioning regimes involve less toxicity, which is important for patients with a disease such as Bare Lymphocyte Syndrome, whose organs can be greatly affected by frequent infections.
Umbilical cord blood transplants, double umbilical cord blood transplants, bone marrow transplants and peripheral blood stem cell transplant will all be tested.
Stem cells are being used in gene therapy, which aims to correct the underlying genetic abnormality by replacing the faulty gene in immune cells with a normal copy. Gene therapy has the potential to offer a gentler option than a stem cell transplant.
Gene therapy involves taking stem cells from a patient’s blood or bone marrow and inserting a normal copy of the defective gene into the DNA. This is usually done with a viral vector. Viruses by their very nature survive and spread by inserting their genes into the host’s genome. As in a stem cell transplant, these new stem cells find their way to the bone marrow, where they start to produce healthy immune cells.
This is known as ‘somatic gene therapy’ – altered genetic material is only present in cells derived from the infused stem cells and cannot be passed on to future generations.
Primary immunodeficiencies have been among the first diseases to undergo gene therapy trials and results have shown much promise. Severe combined immunodeficiency diseases such as ADA-SCID, X-linked SCID and chronic granulomatous disease have shown that they can be cured by gene therapy.
However, serious complications have also arisen. The gammaviral vectors used in early trials have resulted in some patients developing leukaemia. New viral vectors are being developed and patients are now observed for a longer period of time.
Furthermore, a new generation of viral vectors called, SIN or ‘self activation lentiviral vectors’ have been shown to reduce the likelihood of oncogene activation, so may prove to be more beneficial in the long-term. More studies are needed.
The NHS in the UK, is funding gene therapy for the first time to test its safety and efficacy in treating a form of SCID, as reported in October 2017. GSK Strimvelis will receive funding for its gene therapeutic for ADA-SCID in the hope that it will provide a one-off cure for patients in the future.
Several ongoing studies are collecting genetic and patient data for patients with SCID. Examples of this are a study by the National Heart Lung and Blood Institute into the genetic basis of immunodeficiency and the genetic analysis study by the National Institute of Allergies and Infectious Diseases.
The more that is understood about the genetic and molecular make-up of rare diseases, including Bare Lymphocyte Syndrome, the better and more tailored future treatments may become in the future.