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Disorders of the Immune System

4 Pathophysiologic High Yield Cases

A scanning electron microscope image of a single neutrophil (yellow), engulfing anthrax bacteria (orange)

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Disorders of the Immune System -Pathophysiologic High Yield Cases-mic-10-13 1

Disorders of the Immune System

Case 1
A 2-month-old child is admitted to the ICU with fever, hypotension, tachycardia, and lethargy. The medical history is notable for a similar hospitalization at 2 weeks of age. Physical examination is notable for a temperature of 39 C, oral thrush, and rales in the right lung fields. Chest x-ray film reveals multilobar pneumonia. Given the history of recurrent severe infection, the pediatrician suspects an immunodeficiency disorder. Questions A. What is the most likely immunodeficiency in this child? B. What are the underlying genetic and cellular defects associated with this disease? C. What is the overall prognosis for patients with this disorder? A. The most likely cause of this child's recurrent infections is severe combined immunodeficiency disease (SCID). These patients have complete or near-complete failure of development of both cellular and humoral components of the immune system. Placental transfer of maternal immunoglobulin is insufficient to protect these children from infection, and for that reason they present at a very early age with severe infections. B. SCID is a heterogeneous group of genetic and cellular disorders characterized by a failure in the cellular maturation of lymphoid stem cells, resulting in reduced numbers and function of both B and T lymphocytes and hypogammaglobulinemia. The genetic and cellular defects can occur at many different levels, starting with surface membrane receptors, but also including deficiencies in signal transduction or metabolic biochemical pathways. Although the different molecular defects may cause clinically indistinguishable phenotypes, identification of specific mutations allows for improved genetic counseling, prenatal diagnosis, and carrier detection. The most common genetic defect is an X-linked form of SCID in which the maturation defect is mainly in the T-lymphocyte lineage and is due to a point mutation in the chain of the IL-2 receptor. This defective chain is shared by the receptors for IL-4, IL-7, IL-9, and IL-15, leading to dysfunction of all of these cytokine receptors. Defective signaling through the IL-7 receptor appears to block normal maturation of T lymphocytes. Defective IL-2 responses inhibit proliferation of T, B, and NK cells, explaining the combined immune defects seen in XSCID patients.

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Several autosomally inherited defects have also been identified. A defect in the chain of the IL-7 receptor can lead to an autosomal recessive form of SCID through mechanisms similar to XSCID but with intact NK cells. About 20% of SCID cases are caused by a deficiency of adenosine deaminase (ADA), which is an enzyme in the purine salvage pathway, responsible for the metabolism of adenosine. Absence of the ADA enzyme results in an accumulation of toxic adenosine metabolites within the cells. These metabolites inhibit normal lymphocyte proliferation and lead to extreme cytopenia of both B and T lymphocytes. The combined immunologic deficiency and clinical presentation of this disorder, known as SCID-ADA, is identical to that of the other forms of SCID. Skeletal abnormalities and neurologic abnormalities may be associated with this disease. An alternate autosomally recessive form of SCID is a deficiency of ZAP-70, a tyrosine kinase important in normal T-lymphocyte function. Deficiency of this tyrosine kinase results in total absence of CD8 T lymphocytes and functionally defective CD4 T lymphocytes, but normal B-lymphocyte and NK activity. Deficiencies of both p56kk and Jak3 (Janus kinase 3) can also lead to SCID through defective signal transduction; p56kk is a T-cell receptorassociated tyrosine kinase that is essential for T-cell differentiation, activation, and proliferation. Jak3 is a cytokine receptor-associated signaling molecule. Finally, patients have been identified with defective recombination activating gene (RAG-1 and RAG-2) products. RAG-1 and RAG-2 initiate recombination of antigen-binding proteins, immunoglobulins and T-cell receptors. The defect leads to both quantitative and qualitative (functional) deficiencies of T and B lymphocytes. C. Without treatment, most patients with SCID die within the first 1 2 years.

Case 2
An 18-month-old boy is brought to the emergency department by his parents with a high fever, shortness of breath, and cough. The boy was well until he was 6 months old. Since then, he has had four bouts of otitis media, and because of their severity and recurrence, he was placed for several months on prophylactic antibiotics. He was recently taken off the antibiotics to see how he would do. The day before presentation, he developed a cough that has quickly progressed into an illness with high fevers and lethargy. Both of his parents are healthy, and he has a healthy older sister. His father's family history is unremarkable, but his maternal uncle died of pneumonia in infancy. Examination is remarkable for a normally developed toddler who is lethargic and tachypneic. His temperature is 39 C, and he has decreased breath sounds at both lung bases. Chest x-ray film shows consolidation of the right and left lower lobes, as well as bilateral pleural effusions. He is admitted to the hospital, and the boy's blood cultures grow out Streptococcus pneumoniae the next day. Immunologic testing shows very low levels of IgG, IgM, and IgA antibodies in the serum, and flow cytometry shows the absence of circulating B lymphocytes.
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Questions A. What is the likely diagnosis in this patient and why? B. What is the primary pathophysiologic defect in the condition, and how does it lead to this clinical presentation? C. Why are the affected children generally fine until they reach 4 6 months of age? A. This child has X-linked agammaglobinemia, formerly called Bruton's agammaglobinemia. The history of multiple infections occurring after the age of 6 months, the family history of a maternal uncle with lethal infection, the severe current infection with Streptococcus pneumoniae, and the absence of circulating B lymphocytes are characteristic of this disorder. B. The main defect is a mutation in the BTK (Bruton's tyrosine kinase) gene, which is located on the X chromosome. This gene's product is a B-cellspecific signaling protein necessary for normal B-cell maturation. The mutation affects the catalytic domain of the protein, halting B-cell maturation. This, in turn, leads to absence or greatly reduced levels of the immunoglobulins IgA, IgG, and IgM. Their absence or reduction is a particular problem with fighting infections from encapsulated bacteria because these bacteria require antibody binding for efficient opsonization. Therefore, patients are particularly susceptible to infections with bacteria such as Haemophilus influenzae and S pneumoniae. Because they cannot mount an antibody response, they also develop very little immunity to these infections and are thus susceptible to repeated infections with the same organism. C. The affected child is relatively protected by circulating maternal antibodies until 46 months of age. The child's immune system is otherwise unaffected, but as the levels of maternal antibodies decrease, the child becomes increasingly susceptible to infection, particularly from encapsulated bacteria.

Case 3
An 18-year-old man presents with complaints of fever, facial pain, and nasal congestion consistent with a diagnosis of acute sinusitis. His medical history is notable for multiple sinus infections, two episodes of pneumonia, and chronic diarrhea, all suggestive of primary immunodeficiency syndrome. Workup establishes a diagnosis of common variable immunodeficiency. Questions A. What are the common infectious manifestations of common variable immunodeficiency?
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B. What are the underlying immunologic abnormalities responsible for these infectious manifestations? C. What other diseases is this patient at increased risk for? D. What treatment is indicated? A. Individuals with common variable immunodeficiency (CVI) commonly develop recurrent sinopulmonary infections such as sinusitis, otitis media, bronchitis, and pneumonia. Bronchiectasis may develop as a result of these recurrent infections. They may also develop GI malabsorption from bacterial overgrowth or chronic Giardia infection in the small bowel. B. CVI is a heterogeneous disorder in which the primary immunologic abnormality is a marked reduction in antibody production, with normal or reduced numbers of circulating B cells. This is most commonly caused by a defect in the terminal differentiation of B lymphocytes in response to T-lymphocytedependent and T-lymphocyteindependent stimuli. However, defects in B-lymphocyte development have been shown to occur at any stage of the maturation pathway. In approximately 80% of patients, the defect is intrinsic to the B-lymphocyte population. In the rest, a variety of T-cell abnormalities lead to immune defects with subsequent impairment of B-cell differentiation. T-lymphocyte dysfunction can be manifested as increased suppressor T-lymphocyte activity, decreased cytokine production, defective synthesis of B-lymphocyte growth factors, defective cytokine gene expression in T cells, decreased T-cell mitogenesis, and deficient lymphokine activated killer cell function. C. Individuals with CVI are at increased risk of autoimmune disorders and malignancies. The autoimmune disorders most commonly seen in association with CVI include immune thrombocytopenic purpura, hemolytic anemia, and symmetric seronegative arthritis. The malignancies associated with CVI include lymphomas, gastric carcinoma, and skin cancers. D. Treatment is mainly symptomatic along with replacement of immune globulin with monthly infusions of IVIG.

Case 4
A 31-year-old male injection drug user presents to the emergency department with a chief complaint of shortness of breath. He describes a 1-month history of intermittent fevers and night sweats associated with a nonproductive cough. He has become progressively more short of breath, initially only with exertion, but now he feels dyspneic at rest. He appears to be in moderate respiratory distress. His vital signs are abnormal, with fever to 39 C, heart rate of 112 bpm, respiratory rate of 20/minute, and oxygen saturation of 88% on room air. Physical examination is otherwise unremarkable but notable for the absence of abnormal lung sounds. Chest x-ray film reveals a diffuse interstitial infiltrate characteristic of
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pneumocystis pneumonia, an opportunistic infection.

Questions A. What is the underlying disease most likely responsible for this man's susceptibility to pneumocystis pneumonia? B. What is the pathogenesis of the immunosuppression caused by this underlying disease? C. What is the natural history of this disease? What are some of the common clinical manifestations seen during its progression? A. Pneumocystis pneumonia is commonly seen in AIDS. An HIV-1 antibody test should be obtained whenever the diagnosis of Pneumocystis jiroveci is suspected. B. AIDS is the consequence of infection with HIV-1, a retrovirus, which infects multiple cell lines, including lymphocytes, monocytes, macrophages, and dendritic cells. With HIV infection, there is an absolute reduction of CD4 T lymphocytes, an accompanying deficit in CD4 T-lymphocyte function, and an associated increase in CD8 cytotoxic T lymphocytes (CTLs). In addition to the cell-mediated immune defects, B-lymphocyte function is altered such that many infected individuals have marked hypergammaglobulinemia but impaired specific antibody responses. The resultant immunosuppression predisposes patients to the constellation of opportunistic infections that characterizes AIDS. The loss of CD4 cells seen in HIV infection is the result of multiple mechanisms, including (1) autoimmune destruction, (2) direct viral infection and destruction, (3) fusion and formation into multinucleated giant cells, (4) toxicity of viral proteins to CD4 T lymphocytes and hematopoietic precursors, and (5) apoptosis (programmed cell death). C. The clinical manifestations of HIV infection and AIDS are the direct consequence of progressive and severe immunosuppression and can be correlated with the degree of CD4 T-lymphocyte destruction. HIV infection may present as an acute, self-limited febrile syndrome. This is often followed by a long, clinically silent period, sometimes associated with generalized lymphadenopathy. The time course of disease progression may vary; the majority of individuals remain asymptomatic for 510 years. Approximately 70% of HIVinfected individuals will develop AIDS after a decade of infection. Approximately 10% of those infected manifest rapid progression to AIDS within 5 years after infection. A minority of individuals are "long-term nonprogressors." Genetic factors, host cytotoxic immune responses, and viral load and virulence all appear to impact susceptibility to infection and the rate of disease progression. Multidrug antiretroviral therapy has dramatically changed this natural history and markedly prolonged survival.

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As the CD4 count declines, the incidence of infection increases. At CD4 counts between 200/L and 500/L, patients are at an increased risk for bacterial infections, including pneumonia and sinusitis. As CD4 counts continue to dropgenerally below 250/Lthey are at high risk for opportunistic infections such as pneumocystic pneumonia, candidiasis, toxoplasmosis, cryptococcal meningitis, cytomegalovirus (CMV) retinitis, and Mycobacterium avium complex infection. HIV-infected individuals are also at increased risk for certain malignancies, including Kaposi's sarcoma, non-Hodgkin's lymphoma, primary CNS lymphoma, invasive cervical carcinoma, and anal squamous cell carcinoma. Other manifestations of AIDS include AIDS dementia complex, peripheral neuropathy, monoarticular and polyarticular arthritides, unexplained fevers, and weight loss.

Reference: McPhee SJ Hammer GD Pathophysiology of Disease An Introduction to Clinical Medicine, McGraw-Hill Medical; 6 ed. (2009): Ch. 2 Immune System

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