AssessmentsImmunodeficiencies: Combined T-cell and B-cell disorders: Pathology review
USMLE® Step 1 style questions USMLE
A 2-year-old boy is brought to his primary pediatrician for evaluation of recurrent infections. The parents report the patient had two episodes of severe pneumonia, an episode of otitis media, and herpes labialis in the past nine months. He was born at 38 weeks gestation to a 28-year-old otherwise healthy woman. He eats and drinks normally and has achieved the normal developmental milestones. Vitals are within normal limits. Physical examination demonstrates a well-developed and well-nourished child with fair complexion. He has eczema on his cheeks and trunk as well as petechiae on the bilateral lower extremities. Laboratory evaluation reveals a leukocyte count of 8,000/mm3 and a platelet count of 70,000/mm3. Flow cytometry of peripheral lymphocytes reveal absence of the WAS protein. Which of the following immunologic processes is most likely affected given this patient's findings?
Aurora, an 18 month old girl, is brought to the clinic because of frequent respiratory and ear infections. At first glance, you notice she has some small dilated blood vessels over the sclera of her eyes. Upon physical examination, you also realize that she has a delay in speech, as well as frequent stumbling when walking. Laboratory studies are obtained, showing a low lymphocyte count, low immunoglobulin levels, and high alpha-fetoprotein or AFP. Next comes Mathew, a 16 month old boy that’s brought to the clinic because of a skin rash that appeared on his back since infancy and won’t go away. Mathew’s mother also tells you that he has frequent spontaneous nosebleeds, and has had recurrent respiratory tract infections over the last few months. Laboratory studies are obtained, revealing that Mathew’s platelets are quite small in size and fewer than normal, while the immunoglobulins IgA and IgE are increased.
Based on the initial presentation, both cases seem to have some form of combined B- and T-cell disorder causing immunodeficiency, meaning that their immune system's ability to fight pathogens is compromised. Combined B- and T-cell disorders are characterized by defects in the development of both B and T cells, which respectively lead to impaired antibody and cellular immune responses. For your exams, the most high yield combined B- and T-cell disorders include severe combined immunodeficiency, ataxia telangiectasia, hyper IgM syndrome, and Wiskott-Aldrich syndrome.
Okay, then! Starting with severe combined immunodeficiency, or SCID for short, which is the most severe form of primary immunodeficiencies. In fact, the immune system is so dysfunctional that it’s considered almost completely absent.
Now, for your exams, remember that SCID can be caused by mutations in a variety of genes, the most common one codes for the gamma chain of the IL-2 receptor. For your exams, remember that this mutation is X-linked recessive. Okay, now, this protein is a necessary component of the IL-2 receptor, which is involved in lymphocyte maturation and activation. In SCID, the mutated gamma chain leads to the production of a defective IL-2 receptor, and thus a lack of functional mature lymphocytes.
Another high yield form of SCID is ADA deficiency or ADA-SCID, which is caused by an autosomal recessive mutation in the gene coding for adenosine deaminase, or ADA. Now, normally, in the purine salvage pathway, ADA is required to degrade adenosine and deoxyadenosine. As a consequence there’s accumulation of adenosine and deoxyadenosine, and these can be toxic to B and T lymphocytes. In addition, the excess deoxyadenosine gets converted into deoxyadenosine triphosphate or dATP. Accumulation of dATP leads to inhibition of the enzyme ribonucleotide reductase, which mediates the conversion of ribonucleotides to deoxynucleotides. The end result is an impaired DNA synthesis in B and T cells, which leads to failure in their maturation and proliferation.
And a third type of SCID to keep in mind is caused by an autosomal recessive mutation in the recombination-activating genes, or RAG for short. These enzymes are necessary for a process called VDJ recombination, where multiple V, D, and J gene segments in the DNA of T and B cells are randomly recombined to create variability in the T and B cell receptors. So, mutations of the RAG genes prevent VDJ recombination, which means the B and T cell receptors lose their ability to recognize a wide variety of antigens.
Now, regardless of the type of mutation, all forms of SCID typically present in infancy as an extreme susceptibility to all kinds of bacterial, viral, and fungal infections. Most importantly, these include opportunistic pathogens, such as Candida albicans, nontuberculous Mycobacteria, or Pneumocystis jirovecii, which don’t usually cause serious infections in individuals with a healthy immune system. For your exams, remember that oral candidiasis presents with a characteristic oral thrush that’s often described as “cottage cheese-like thrush”, isn’t painful, and can be scraped away with a tongue depressor, leaving behind a red mucosal base which sometimes bleeds. In addition, individuals often present with chronic diarrhea, and a failure to thrive. If left untreated, SCID has a high mortality rate in the first year of life.
Diagnosis of SCID in many countries is based on newborn screening tests. These measure T-cell receptor excision circles, or TRECs, in blood. The presence of TRECs is a biomarker for normal T-cell development, so remember that in SCID, TRECs are absent. Laboratory tests are also required, showing an absolute lymphocyte count lower than 2500 cells per cubic millimeter, with T cells making up less than 20 percent of the total lymphocytes in flow cytometry. Additional findings can include absence of thymic shadow on chest X-rays, as T cell maturation normally takes place in the thymus. A lymph node biopsy shows absence of germinal centers, which is where mature B cells would normally proliferate to fight infections. Finally, to identify the specific form of SCID, genetic testing can be performed to look for the mutated gene.
For treatment, hematopoietic stem cell transplantation is recommended before 3 month of age. Until then, these infants are often kept in a sterile environment to prevent infections. In addition, intravenous IgG infusions can be given about once a month to help boost their immune system.
Next up, there’s ataxia telangiectasia, where ataxia refers to poor coordination and telangiectasia refers to dilated blood vessels, and these are the two key symptoms of this disease. Ataxia telangiectasia develops due to a genetic mutation in the ATM gene, which codes for a protein called ataxia telangiectasia mutated kinase, or ATM kinase for short. Normally, the DNA of the cells in the body gets damaged throughout their lifespan. This can happen upon cell division, as well as from various environmental factors like ionizing radiation. When there’s some kind of DNA damage, ATM kinase activates other proteins, which will either fix the DNA or kill the affected cell. Now, for your exams, keep in mind that ATM is particularly important for the development of B- and T lymphocytes, since these cells are constantly dividing and rearranging their DNA to recognize a wide variety of antigens. So this means they’re much more prone to DNA damage as a result!
In ataxia telangiectasia, cells don't have sufficient ATM to properly repair the damaged DNA. As a result, some of the defective cells might continue to grow and proliferate despite the mutations in their DNA. This leads to accumulation of mutations in future cells, which makes these individuals more prone to develop cancers, such as leukemias and lymphomas, especially after exposure to ionizing radiation, like X-rays. And that’s a high yield fact!
Now, some cells with damaged DNA will simply die. This can especially impact the nervous system. When the cerebellum’s affected, which is the part of the brain that coordinates movement, it atrophies, leading to ataxia or difficulty with coordination and movement. In terms of symptoms, ataxia can first manifest in infants or toddlers as a delay in reaching certain developmental milestones, such as sitting or walking. As these children grow up, they can present with frequent stumbling or unsteady gait, and trouble with fine motor movements like those needed for writing or eye movement. In addition, individuals can have difficulty with speech or swallowing, which can cause aspiration pneumonia. That’s where bits of food or liquids are able to enter the airways, and cause direct damage as well as infections in the lungs.
Now, a high yield fact is that these individuals may also develop recurrent infections, especially of the respiratory tract, because of the defects in B- and T-cell development
Last but not least, for reasons we don't really know, most individuals affected by ataxia telangiectasia develop, well, telangiectasias, also called spider angiomas. In a test question, look for a picture with dilated blood vessels visible especially on the sclera of the eyes.
- "Robbins Basic Pathology" Elsevier (2017)
- "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2)" McGraw-Hill Education / Medical (2018)
- "Educational paper" European Journal of Pediatrics (2011)
- "Severe Combined Immunodeficiences: New and Old Scenarios" International Reviews of Immunology (2012)
- "Sur un syndrome progressif comprenant des télangiectasies capillaires cutanées et conjonctivales symétriques, à disposition naevoïde et des troubles cérébelleux" Stereotactic and Functional Neurosurgery (1941)
- "Ataxia-telangiectasia: an overview 19:1-63" Kroc Found Ser (1985)
- "Localization of an ataxia-telangiectasia gene to chromosome 11q22-23." Nature. 336(6199):577-580 (1988)
- "Advances in Cancer Research" G.F.V. (2001)
- "Pedigree demonstrating a sex-linked recessive condition characterized by draining ears, eczematoid dermatitis and bloody diarrhea 13(2):133-139" Pediatrics (1954)
- "Primary immunodeficiencies associated with eosinophilia" Allergy, Asthma & Clinical Immunology (2016)