Saturday, February 13, 2016

Rare Immune Diseases (what they tell us)

Humans have three evolved immune systems: innate, intrinsic, and adaptive. The innate immune system is an ancient and somewhat non-specific mechanism deployed by plants, fungi, insects, and most multicellular organisms, including humans (1). This system recruits immune cells to sites of infection, using a protein complex expressed by white blood cells, known as the inflammasome. Some inflammasome proteins are caspase 1 and 5, PYCARD, and NALP. The inflammasome promotes a variety of chemical mediators known as cytokines. Innate immunity includes the complement system, which acts to clear dead cells. It also includes the macrophage system, which engulfs and removes foreign materials.

The intrinsic immune system is a cell-based (i.e., not humoral) anti-viral mechanism that is always "on" (i.e., not activated by the presence of its target, as seen in adaptive immunity and innate immunity) (2). Intrinsic immunity has been studied for its role in controlling retrovirus infections (e.g. HIV infection). It is known that intrinsic immunity is not restricted to retroviruses, but its role in blocking infection by other classes of virus is still largely unknown and unstudied. Intrinsic immunity is a newly-discovered immune response system, about which we have much to learn. One question: Is the intrinsic immune response available to all cell types, or is it strictly restricted to specific responder cells, as is the case with innate immunity and adaptive immunity?

The adaptive immune system adapts to the specific chemical properties of foreign antigens, such as those that appear on viruses and other infectious agents. Adaptive immunity is a system wherein somatic T cells and B cells are produced, each with a unique and characteristic immunoglobulin (in the case of B cells) or T-cell receptor (in the case of T cells). Through a complex presentation and selection system, a foreign antigen elicits the replication of a B cell whose unique immunoglobulin molecule (i.e., so-called antibodies) matches the antigen. Secretion of matching antibodies leads to the production of antigen-antibody complexes that may deactivate and clear circulating antibodies, or may lead to the destruction of the organism that carries the antigen (e.g., virus or bacteria). To produce the many unique B and T cells, each with a uniquely rearranged segment of DNA that encodes specific immunoglobulins or T-cell receptors, recombination and hypermutation take place within a specific gene region. This process yields on the order of a billion unique somatic genes, starting with one germinal genome. This amazing show of genetic heterogeneity requires the participation of recombination activating genes (i.e., RAGs). The acquisition of an immunologically active recombination activating gene is presumed to be the key evolutionary event that led to the development of the adaptive immune system that is present in all jawed vertebrates (i.e., gnathostomes). In addition,a specialized method of processing immunoglobulin heavy chain mRNA transcript accounts for the high levels of secretion of immunoglobulin proteins by plasma cells (3). As one might expect, inherited mutations in RAG genes cause immune deficiency syndromes (4), (5).

We learn about the immune system by studying rare diseases. Here are just a few examples of inherited immune deficiency diseases:

- Ataxia-telangiectasia is caused by a defect in the ATM gene. The ATM gene produce regulates a variety of cellular responses to stress, and orchestrates the complex repair of double-stranded breaks in DNA (6). Ataxia telangectasia is a syndrome involving several organs and physiologic systems. As its name suggests, it causes ataxia (i.e., imbalanced gait) due to degenerative changes in the cerebellum. It also produces focal areas of small vessel dilation (i.e., telangiectasias). The majority of affected individuals have immune deficits, usually manifested as low levels of immunoglobulins, poor antibody response to vaccines, and a reduction in circulating lymphocytes. Like patients with selective IgA deficiency (vida infra), they are prone to ear, sinus, and lung infections.

- Chronic granulomatous disease is a genetically heterogeneous group of childhood immune-deficiencies that are all caused by an inability of neutrophils and macrophages to produce a so-call "respiratory burst". The respiratory burst involves production of reactive oxygen species that are toxic to ingested organisms (e.g., bacteria and fungi). Without the respiratory burst, ingested organisms persist, and white blood cells are persistently attracted to the site of infection, eventually producing a granuloma (i.e., a collection of macrophages, and fibrocytes with some acute and chronic inflammatory cells). Catalase-positive organisms are most likely to cause infections in individuals with chronic granulomatous diseases, as these organisms will break down hydrogen peroxide, a respiratory burst molecule, thus exacerbating the deficiency. Studies of chronic granulomatous disease have elucidated some of the important components of the "respiratory burst" pathway and have taught us how ingested organisms are killed inside neutrophils and macrophages (7).

- DiGeorge syndrome is caused by a small deletion of chromosome 22. As one might expect, the loss of a stretch of genes encompassing 3 million base pairs results in developmental anomalies in several organs. The immune deficit is a consequence of thymic hypoplasia. Observations on children with Di George syndrome have added enormously to our understanding of the crucial role of the neonatal thymus in the growth and maturation of T cells.

- Haim-Munk syndrome, Papillon-Lefevre syndrome, perpubertal periodontitis, and aggressive periodontitis are all characterized by early periodoontitis, and all are caused by cathepsin C gene mutations (8). Cathepsin C is a lysosomal proteinase with high activity in inflammatory cells. It is highly expressed in gingival epithelium, where a reduction in its normal activity seems to encourage the emergence of opportunistic infections (8).

- Hyper IgM syndrome is an immunodeficiency disease that results from an inability of B cells to produce classes of immunoglobulins other than IgM. IgM is the default immunoglobulin produced by B cells. A vigorous B cell response to antigens requires a switch from IgM synthesis over to the other immunoglobulins (e.g., IgG, IgA, IgE). The switching system is complex, and mutations of various different genes expressed in T cells or B cells, can cause the hyper IgM syndrome (e.g., CD40LG gene, AICDA gene, CD40 gene, UNG gene). The genes involved in the switching system may also be involved in other pathways used by T or B cells, to induce a combined immunodeficiency syndrome in which hyper IgM is just one component (9).

- Hyperimmunoglobulin E syndrome, also known as Hyper IgE recurrent infection syndrome, is characterized by immunodeficiency, recurrent infections, often involving the skin and the lungs, and a variety of skeletal and connective tissue abnormalities (10). Most prominent on physical examination of children with the disease is a double row of teeth, due to failure of the primary teeth to extrude when the permanent teeth grow in. Because the skin infections may occur as boils, another synonym for this diseases is Job's syndrome (a trope to the biblical story of Job, and his affliction with boils). The genetic condition is somewhat heterogeneous, with most cases caused by mutations in the STAT3 (Signal Transducer and Activator of Transcription 3) gene, while others are caused by Tyk2 mutations as well as currently undetermined mutations in other genes. Another immunodeficiency syndrome, familial chronic mucocutaneous candidiasis-7 is caused by heterozygous mutation in the STAT1 gene. In any case, individuals who have hyperimmunoglobulin E syndrome are caught in a pleiotropic storm produced by alterations in STAT3 pathways that yield a wide variety of developmental and immunologic manifestations. In their review paper on the Hyper IgE Syndromes, Alexandra Freeman and Steven Holland concluded, "Understanding how STAT3 deficiency leads to the many facets of this disease will hopefully help us understand diseases that are more common, such as idiopathic scoliosis, atopic dermatitis, staphylococcal skin abscesses, and the coronary artery aneurysms of Kawasaki disease" (10).

- Immunodeficiency-centromeric instability-facial anomalies syndrome types 1 and 2 are caused by mutation in the DNMT3B gene and in the ZBTB24 gene, respectively. These two diseases are clinically identical and are characterized by an immunoglobulin deficiency resulting in recurrent infections, facial abnormalities, and mental retardation.

- Recurrent invasive pneumococcal infections in a child or adolescent may indicate a deficiency of the innate immune system. Inherited susceptibility to invasive pneumococcal infections can be caused by mutations in genes encoding innate system protein (e.g., IRAK4 gene, NEMO gene) (11). Conversely, an advantageous polymorphism in the innate system's TIRAP gene (Toll-Interleukin 1 Receptor Protein) confers protection against infections from invasive pneumococcal disease, bacteremia, malaria and tuberculosis (12).

- Selective immunoglobulin A deficiency is the most common defect of humoral immunity, and is characterized by a deficiency of immunoglobulin A (IgA). IgA is an immunoglobulin primarily synthesized by mucosa-lining lymphoid tissue, such as the lymphoid tissue lining the nasal, oral, bronchial and gastrointestinal mucosal surfaces. It is unusual among the immunoglobulins because it is secreted onto an epithelial surface, rather than being absorbed directly into the blood stream. As you might expect, individuals with IgA deficiency are susceptible to recurring sino-pulmonary and gastrointestinal infections.

- Severe combined immunodeficiency is a collection of rare congenital disorders characterized by deficiencies of T and B cells, and all are caused, ultimately, by a defect in hematopoietic stem cells. Each type of SCID is caused by a type-specific gene defect (e.g., the gene that encodes IL-7 receptor, a gene defect that results in gamma chain deficiency, a recombination activating gene deficiency, and the gene encoding adenine deaminase). The SCID diseases illustrate how different genetic defects can lead through different pathways to a common clinical phenotype.

- WHIM syndrome (Warts, Hypogammaglobulinemia, Infections and Myelokathexis) is a combined immunodeficiency disease caused by an alteration in the chemokine receptor gene CXCR4 (13). Warts result from a lowered immune repression of papillomaviruses. Likewise, the other phenotypic components of the disease arise from the aberrant chemokine receptor, including myelokathexis, a congenital cytopenia of white cells.

- Wiskott-Aldrich syndrome is characterized by eczema, a low platelet count and small platelets, and a combined immunodeficiency, involving B cells and T cells. Most affected individuals develop an autoimmune disease, and there is an increased risk of developing lymphoma or leukemia. The disease is caused by a aberration in the WASp gene, encoding a pleiotropic protein expressed in high levels in hematopoietic cells. The expressed protein plays a role in actin polymerization. A normal actin cytoskeleton is necessary for a proper immune synapse, wherein a target antigen-carrying cell and an effector lymphocyte meet, initiating a process in which an antigen-specific response is attained.

- X-linked agammaglobulinemia, also known as Bruton type agammaglobulinemia, was first described in 1952, and was the first known immunodeficiency disease (14). The disease occurs in sons of female carriers, and produces severe infections beginning in early childhood. It is caused by an inherited deficiency in a tyrosine kinase enzyme required for normal B-cell maturation. B-cells are not produced; hence immunoglobulins are not produced, resulting in a deficiency of antibody-mediated adaptive immunity. Knowledge of of the pathogenesis of X-linked agammaglobulinemia has advanced our understanding of the role of the B cell in immunity.

- Common Variable ImmunoDeficiency (CVID) is somewhat of a misnomer. CVID represents a collection of about 150 rare genetic immune disorders. The "common" phenotypic feature of CVID is that all of the included disorders are characterized by hypoglobulinemia (i.e., low levels of IgA, IgG, or one of the other immunoglobulin types). The inclusion of deficiencies of variable types of immunoglobulin molecule accounts for the "variable" in its name. Another name for this condition is "Acquired hypogammaglobulinemia," also a poor choice of terminology. The term "Acquired" is applied to the disorder because the majority of patients seem to develop their disease between the ages of 20 and 40, indicating that something happened in the first few decades of life that led to the acquisition of the condition. This is not the case. The disease, even in its so-called acquired form, manifests as gradually diminishing IgG levels beginning in early childhood, becoming clinically evident in early adulthood (15). CVID, even in the aggregate of all its included disorders, is a rare condition, with a prevalence of about 1 in 50,000. Though rare, CVID is the most commonly diagnosed immune disorder of humans.

Though immunodeficiency diseases are rare, infectious diseases are common. Why do we humans develop infectious diseases when we have three separate immune systems to protect us? As animals have developed elaborate defense systems, the organisms that cause disease have developed even more effective attack systems. Small chinks in our immune defenses can open the gates to an infectious disease. Starvation, concurrent disease, extreme youth, extreme age, and any cause of cytopenia (i.e., reduction in circulating blood cells), can all lower our resistance to disease. In addition, it would seem that complex sets of genes predispose otherwise healthy individuals to specific types of infections.

Rule - Immune deficits are usually polygenic or have an environmental contribution.
Brief Rationale - We are constantly being reminded of Darwin's cruel game; monogenic causes of immunosufficiency are rare because they reduce fitness. Infectious disease are extremely common, and every infectious disease marks a defeat in the human body's battle against invasive organisms. When we study families with increased susceptibility to certain types of infection, we seldom observe Mendelian patterns of inheritance; instead, we observe non-Mendelian pattern indicative of polygenic inheritance (16). Though there are dozens or monogenic immunodeficiency syndromes, they account for a very small fraction of the instances of immune deficiency in the general population.

Sets of variant genes can produce some increase in the risk of infections. Among these variant genes, CISH (cytokine-inducible SRC homology 2 domain) polymorphisms seem to play a significant role. CISH protein variants can increase susceptibility to bacteremia, malaria, and tuberculosis by about 18% (17).

- Jules Berman (copyrighted material)

key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, disease complexity, immunity, jules j berman

Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.


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[2] Yan N, Chen ZJ. Intrinsic antiviral immunity. Nat Immunol 13:214-222, 2012.

[3] Borghesi L, Milcarek C.From B cell to plasma cell: regulation of V(D)J recombination and antibody secretion. Immunol Res 36:27-32, 2006.

[4] Zhang J, Quintal L, Atkinson A, Williams B, Grunebaum E, Roifman CM. Novel RAG1 mutation in a case of severe combined immunodeficiency. Pediatrics 116:445-449,2005.

[5] de Villartay JP, Lim A, Al-Mousa H, Dupont S, D chanet-Merville J, Coumau-Gatbois E, et al. A novel immunodeficiency associated with hypomorphic RAG1 mutations and CMV infection. J Clin Invest 115:3291-3299, 2005.

[6] Shiloh Y, Kastan MB. ATM: genome stability, neuronal development, and cancer cross paths. Advances in Cancer Research 83: 209-254, 2001.

[7] Heyworth PG, Cross AR, Curnutte JT. Chronic granulomatous disease. Curr Opin Immunol 15:578-584, 2003.

[8] Hart TC, Hart PS, Michalec MD, Zhang Y, Firatli E, Van Dyke TE, et al. Haim-Munk syndrome and Papillon-Lefevre syndrome are allelic mutations in cathepsin C. J Med Genet 37:88-94, 2000.

[9] Lougaris V, Badolato R, Ferrari S, Plebani A. Hyper immunoglobulin M syndrome due to CD40 deficiency: clinical, molecular, and immunological features. Immunol Rev 203:48-66, 2005.

[10] Freeman AF, Holland SM. The hyper-IgE syndromes. Immunol Allergy Clin North Am 28:277-291, 2008.

[11] Ku CL, Picard C, Erd s M, Jeurissen A, Bustamante J, Puel A, et al. IRAK4 and NEMO mutations in otherwise healthy children with recurrent invasive pneumococcal disease. J Med Genet 44:16-23, 2007.

[12] Khor CC, Chapman SJ, Vannberg FO, Dunne A, Murphy C, Ling EY, et al. A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis. Nat Genet 39:523-528, 2007.

[13] Hernandez PA, Gorlin RJ, Lukens JN, Taniuchi S, Bohinjec J, Francois F, et al. Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Nat Genet 34:70-74, 2003.

[14] Bruton OC. Agammaglobulinemia. Pediatrics 9:722-728, 1952.

[15] Park JH, Resnick ES, Cunningham-Rundles C. Perspectives on common variable immune deficiency. Ann NY Acad Sci 1246:41-49, 2011.

[16] Hill AVS. Evolution, revolution and heresy in the genetics of infectious disease susceptibility. Philos Trans R Soc Lond B Biol Sci 367:840-849, 2012.

[17] Khor CC, Vannberg FO, Chapman SJ, Guo H, Wong SH, Walley AJ, et al. CISH and susceptibility to infectious diseases. N Engl J Med 362:2092-2101, 2010.