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Pathology - C5 Deficiency
Disorder of the complement system specifically C5 deficiency, leading to bacterial meningitis from Neisseria meningitidis . Complement deficits can result in disruption of the traditional route (C1q, C1r, C1s, C2, and C4), which result in respiratory tract or tissue-invasive bacterial infections, usually by Streptococcus pneumoniae , and can culminate in septicemia. Defects in the alternative pathway (C5, C6, C7, C8, and C9) result in susceptibility to N. gonorrhoeae or N. meningitidis infections. In this example, the patient’s lethargy, fever, vomiting, headache, and positive Brudzinski’s sign (reflexive hip flexion with passive neck flexion) hint toward meningitis.
A petechial eruption is symptomatic of N. meningitidis infection and gram-negative diplococci in the CSF corroborate the diagnosis. Functional assays can examine the status of classic and alternative complement pathways, and determination of relative components status can provide a diagnosis. Rarely, a life-threatening and often deadly complication known as Waterhouse–Friderichsen syndrome can emerge due to bleeding within the adrenal glands attributable to N. meningitidis infection.
Disorder of the complement system specifically C5 deficiency, leading to bacterial meningitis from Neisseria meningitidis . Complement deficits can result in disruption of the traditional route (C1q, C1r, C1s, C2, and C4), which result in respiratory tract or tissue-invasive bacterial infections, usually by Streptococcus pneumoniae , and can culminate in septicemia. Defects in the alternative pathway (C5, C6, C7, C8, and C9) result in susceptibility to N. gonorrhoeae or N. meningitidis infections. In this example, the patient’s lethargy, fever, vomiting, headache, and positive Brudzinski’s sign (reflexive hip flexion with passive neck flexion) hint toward meningitis.
A petechial eruption is symptomatic of N. meningitidis infection and gram-negative diplococci in the CSF corroborate the diagnosis. Functional assays can examine the status of classic and alternative complement pathways, and determination of relative components status can provide a diagnosis. Rarely, a life-threatening and often deadly complication known as Waterhouse–Friderichsen syndrome can emerge due to bleeding within the adrenal glands attributable to N. meningitidis infection.
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Pathology - Leukocyte Adhesion Defect
Leukocyte adhesion defect is a rare autosomal recessive disorder that comes from mutations of either integrin-mediated leukocyte adhesion (β2 integrin subunit deficiency) or selectin-mediated leukocyte rolling. Thus, neutrophils are not able to connect to the endothelium and undergo diapedesis to reach affected tissues, hence patients are susceptible to bacterial and fungal infections. Significantly high amounts of blood leukocytes are discovered due to the inability of neutrophils to escape the blood arteries. Impaired wound healing with the absence of pus is characteristic.
A crucial discovery in this condition is delayed loss of the umbilical chord. Hematopoietic stem cell transplantation may be required in severe types. Currently, bone marrow transplantation is the only curative treatment, however gene therapy may be a possibility in the future.
Leukocyte adhesion defect is a rare autosomal recessive disorder that comes from mutations of either integrin-mediated leukocyte adhesion (β2 integrin subunit deficiency) or selectin-mediated leukocyte rolling. Thus, neutrophils are not able to connect to the endothelium and undergo diapedesis to reach affected tissues, hence patients are susceptible to bacterial and fungal infections. Significantly high amounts of blood leukocytes are discovered due to the inability of neutrophils to escape the blood arteries. Impaired wound healing with the absence of pus is characteristic.
A crucial discovery in this condition is delayed loss of the umbilical chord. Hematopoietic stem cell transplantation may be required in severe types. Currently, bone marrow transplantation is the only curative treatment, however gene therapy may be a possibility in the future.
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Pathology - Chronic Granulomatous Disease
Chronic granulomatous disease (CGD) is an X-linked recessive condition. Like with other autoimmune disorders, the sorts of microorganisms that infect the patient hint to the deficiency in the immune response. A patient with CGD will have recurrent infections from fungus and staphylococcus (gram-positive cocci in clusters). The deficiency in CGD is inadequate nicotine adenine dinucleotide phosphate oxidase in neutrophil and monocyte cell membranes, resulting to suppressed superoxide dismutase activity and lowered hydrogen peroxide levels. This limits free-radical generation and resulting in an absence respiratory burst, such that phagocytized catalase-positive bacteria are not destroyed. The diagnosis of CGD can be made by the laboratory observation of neutrophils and macrophages failing to decrease a nitroblue tetrazolium dye (leukocytes with an intact respiratory burst create a blue color upon incubation). Myeloperoxidase deficiency, which is a more common abnormality, is characterized by a normal respiratory burst but absence of hypochlorous acid (bleach) synthesis. The only clinical importance, however, shows in vulnerable patients with DM through significant candidal infections.
Chronic granulomatous disease (CGD) is an X-linked recessive condition. Like with other autoimmune disorders, the sorts of microorganisms that infect the patient hint to the deficiency in the immune response. A patient with CGD will have recurrent infections from fungus and staphylococcus (gram-positive cocci in clusters). The deficiency in CGD is inadequate nicotine adenine dinucleotide phosphate oxidase in neutrophil and monocyte cell membranes, resulting to suppressed superoxide dismutase activity and lowered hydrogen peroxide levels. This limits free-radical generation and resulting in an absence respiratory burst, such that phagocytized catalase-positive bacteria are not destroyed. The diagnosis of CGD can be made by the laboratory observation of neutrophils and macrophages failing to decrease a nitroblue tetrazolium dye (leukocytes with an intact respiratory burst create a blue color upon incubation). Myeloperoxidase deficiency, which is a more common abnormality, is characterized by a normal respiratory burst but absence of hypochlorous acid (bleach) synthesis. The only clinical importance, however, shows in vulnerable patients with DM through significant candidal infections.
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Pathology - DiGeorge Syndrome
congenital thymic aplasia is more often known as DiGeorge syndrome. The condition originates from a failure of the third and fourth pharyngeal pouches to form, resulting in absence of the thymus and parathyroid glands. CATCH-22 is a famous mnemonic used to memorize the clinical signs of the condition. The primary findings are connected to C ardiac defects, as suggested by this patient’s typical ventricular septal defect murmur, as well as A bnormal midline features, including the facial traits mentioned in this patient. Failure of T hymic development results in absence of T cells and susceptibility to opportunistic pathogens, particularly P. jirovecii . C left palate is also a common finding. The lack of PTH can generate symptomatic H ypocalcemia and tetany, as evidenced by the positive Trousseau’s sign (carpal and phalangeal spasm) when the blood pressure cuff is inflated on the patient. The normal genetic mutation is not inherited, but rather a random deletion of the long arm on chromosome 22 (22q11.2 deletion). Live vaccines (e.g., measles, small pox, varicella) are contraindicated. Presentation can be as severe as those of SCID. Therapy involves antimicrobial prophylaxis and thymic transplantation, however the risk of graft-versus-host disease (GVHD) is substantial.
congenital thymic aplasia is more often known as DiGeorge syndrome. The condition originates from a failure of the third and fourth pharyngeal pouches to form, resulting in absence of the thymus and parathyroid glands. CATCH-22 is a famous mnemonic used to memorize the clinical signs of the condition. The primary findings are connected to C ardiac defects, as suggested by this patient’s typical ventricular septal defect murmur, as well as A bnormal midline features, including the facial traits mentioned in this patient. Failure of T hymic development results in absence of T cells and susceptibility to opportunistic pathogens, particularly P. jirovecii . C left palate is also a common finding. The lack of PTH can generate symptomatic H ypocalcemia and tetany, as evidenced by the positive Trousseau’s sign (carpal and phalangeal spasm) when the blood pressure cuff is inflated on the patient. The normal genetic mutation is not inherited, but rather a random deletion of the long arm on chromosome 22 (22q11.2 deletion). Live vaccines (e.g., measles, small pox, varicella) are contraindicated. Presentation can be as severe as those of SCID. Therapy involves antimicrobial prophylaxis and thymic transplantation, however the risk of graft-versus-host disease (GVHD) is substantial.
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Pathology - Ataxia Telangiectasia Syndrome
Ataxia-telangiectasia syndrome is an autosomal recessive disorder stemming from a deficiency in DNA damage repair. Specifically, the ataxia-telangiectasia gene (ATM) is mutated. This gene encodes a protein, which normally serves as a regulator of cell-cycle checkpoints to give time for repair of double-stranded DNA breaks.
This abnormality results in deficient cellular immunity and humoral immunodeficiency with thymic hypoplasia due to the fragile chromosomes that are created within the cells. Instability of the chromosomes also puts patients at increased risk for lymphomas and leukemias. Patients will typically present after the first year of life, when they will be delayed in walking secondary to ataxia. The ataxia occurs subsequent to atrophy of the cerebellum, which normally functions to coordinate balance (in conjunction with the vestibular system) and fine motor control. Oculomotor apraxia, which is difficulties with coordinated head and eye movements, can appear as an inability to track objects in young children. Speech will likely also fail to develop adequately. Patients will exhibit characteristic ocular and cutaneous telangiectasias, which are dilated blood vessels. In addition to decreased IgE and IgA, they also interestingly have raised serum alpha-fetoprotein. Patients with Friedrich’s ataxia, which can present similarly, can be separated from ataxia-telangiectasia syndrome because those patients will not have signs of oculomotor apraxia or the immunologic abnormalities.
Ataxia-telangiectasia syndrome is an autosomal recessive disorder stemming from a deficiency in DNA damage repair. Specifically, the ataxia-telangiectasia gene (ATM) is mutated. This gene encodes a protein, which normally serves as a regulator of cell-cycle checkpoints to give time for repair of double-stranded DNA breaks.
This abnormality results in deficient cellular immunity and humoral immunodeficiency with thymic hypoplasia due to the fragile chromosomes that are created within the cells. Instability of the chromosomes also puts patients at increased risk for lymphomas and leukemias. Patients will typically present after the first year of life, when they will be delayed in walking secondary to ataxia. The ataxia occurs subsequent to atrophy of the cerebellum, which normally functions to coordinate balance (in conjunction with the vestibular system) and fine motor control. Oculomotor apraxia, which is difficulties with coordinated head and eye movements, can appear as an inability to track objects in young children. Speech will likely also fail to develop adequately. Patients will exhibit characteristic ocular and cutaneous telangiectasias, which are dilated blood vessels. In addition to decreased IgE and IgA, they also interestingly have raised serum alpha-fetoprotein. Patients with Friedrich’s ataxia, which can present similarly, can be separated from ataxia-telangiectasia syndrome because those patients will not have signs of oculomotor apraxia or the immunologic abnormalities.
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Pathology - Wiskott - Aldrich Syndrome
Symptomatic triad of Wiskott–Aldrich syndrome (WAS) involves T hrombocytopenia, recurrent sinopulmonary I nfections, and E czema (mnemonic: TIE). WAS is an X-linked recessive disorder characterized by poor cell-mediated immunity and decreased IgM production through gradual deletion of T and B cells. The pathogenesis comes from a null-mutation in the gene that codes the WAS protein (WASP), a regulator of actin polymerization in hematopoietic cells. This leads in the absence of a particular glycoprotein receptor on T cells and platelets, resulting to a poor response to polysaccharide vaccines and to thrombocytopenia, respectively.
Megakaryocyte levels are typical. Splenomegaly can arise attributable to splenic sequestration of platelets, due to the faulty receptor and so contributing to the thrombocytopenia. Petechiae are small hemorrhages within the skin that are a sign of reduced platelets. Levels of IgG will be normal and IgA and IgE may be normal or elevated. Patients are prone to bacterial, viral, and fungal infections and also have a high frequency of autoimmune diseases and lymphoreticular cancers. Bone marrow transplantation may be useful as treatment.
Symptomatic triad of Wiskott–Aldrich syndrome (WAS) involves T hrombocytopenia, recurrent sinopulmonary I nfections, and E czema (mnemonic: TIE). WAS is an X-linked recessive disorder characterized by poor cell-mediated immunity and decreased IgM production through gradual deletion of T and B cells. The pathogenesis comes from a null-mutation in the gene that codes the WAS protein (WASP), a regulator of actin polymerization in hematopoietic cells. This leads in the absence of a particular glycoprotein receptor on T cells and platelets, resulting to a poor response to polysaccharide vaccines and to thrombocytopenia, respectively.
Megakaryocyte levels are typical. Splenomegaly can arise attributable to splenic sequestration of platelets, due to the faulty receptor and so contributing to the thrombocytopenia. Petechiae are small hemorrhages within the skin that are a sign of reduced platelets. Levels of IgG will be normal and IgA and IgE may be normal or elevated. Patients are prone to bacterial, viral, and fungal infections and also have a high frequency of autoimmune diseases and lymphoreticular cancers. Bone marrow transplantation may be useful as treatment.
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Pathology - Severe Combined Immunodeficiency Disease
SCID occurs from a genetic abnormality in stem cells, resulting in absence of the thymus and T and B lymphocytes. In one-half of patients, an autosomal recessive transmission results in the loss of adenosine deaminase, an enzyme involved in purine catabolism. This leads in an accumulation of hazardous deoxyadenosine triphosphate, blocking ribonucleotide reductase and limiting DNA synthesis and therefore lymphocyte proliferation. In other cases, an X-linked transmission leads in absent gamma chain of the interleukin receptor, slowing lymphocyte growth due to issues with interleukin signaling. These patients will present with recurring bacterial, viral, parasite, and fungal infections at a relatively young age; however, maternal antibodies may delay commencement by a few months. Infections will become quite dangerous and include pneumonia, bacteremia, sepsis, and meningitis. Life span is often very short without treatment; however, early discovery and treatment with gene therapy and bone marrow transplantation can be curative.
SCID occurs from a genetic abnormality in stem cells, resulting in absence of the thymus and T and B lymphocytes. In one-half of patients, an autosomal recessive transmission results in the loss of adenosine deaminase, an enzyme involved in purine catabolism. This leads in an accumulation of hazardous deoxyadenosine triphosphate, blocking ribonucleotide reductase and limiting DNA synthesis and therefore lymphocyte proliferation. In other cases, an X-linked transmission leads in absent gamma chain of the interleukin receptor, slowing lymphocyte growth due to issues with interleukin signaling. These patients will present with recurring bacterial, viral, parasite, and fungal infections at a relatively young age; however, maternal antibodies may delay commencement by a few months. Infections will become quite dangerous and include pneumonia, bacteremia, sepsis, and meningitis. Life span is often very short without treatment; however, early discovery and treatment with gene therapy and bone marrow transplantation can be curative.
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Pathology - Bruton's Agammaglobulinemia
Bruton’s agammaglobulinemia is an X-linked recessive illness caused by loss of a tyrosine kinase (Btk) gene, leading in the failure of pre-B cells to grow into mature B cells. All patients will be male and typically begin presenting with illnesses around about 6 months of age, when maternal antibody protection ends. Recurrent febrile sinopulmonary infections owing to pneumococcus and Haemophilus are prevalent. Patients may be noticed to have absent tonsils, as in this example, due to lack of lymphoproliferative germinal centers. Laboratory investigations will show absence of B cells on peripheral smear, and immunoglobulin electrophoresis will demonstrate a severely reduced immunoglobulin level, usually at 10% or less of the normal value.
Bruton’s agammaglobulinemia is an X-linked recessive illness caused by loss of a tyrosine kinase (Btk) gene, leading in the failure of pre-B cells to grow into mature B cells. All patients will be male and typically begin presenting with illnesses around about 6 months of age, when maternal antibody protection ends. Recurrent febrile sinopulmonary infections owing to pneumococcus and Haemophilus are prevalent. Patients may be noticed to have absent tonsils, as in this example, due to lack of lymphoproliferative germinal centers. Laboratory investigations will show absence of B cells on peripheral smear, and immunoglobulin electrophoresis will demonstrate a severely reduced immunoglobulin level, usually at 10% or less of the normal value.
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Pathology - Allergic Rhinitis
This condition is characterized by a Type I (IgE-mediated) acute hypersensitivity reaction to environmental allergens. Patients will often have a personal or family history of other atopic diseases such as asthma or atopic dermatitis. The syndrome is marked by a predisposition to produce IgE antibodies to environmental antigens. As these antigens are filtered by the nasal airways, interaction with surface-bound IgE antibodies on mast cells and basophils triggers a release of preformed mediators and the de novo synthesis of additional mediators, as well as the creation and release of proinflammatory cytokines. Interaction of mediators induces a complicated reaction in target organs, which includes the release of histamine and other stored mediators in the initiation of a complex cascade of actions. Frequent or persistent exposure leads to mucus hypersecretion, IgE production, eosinophilia, and tissue damage. Patients will most usually appear with congestion, clear nasal discharge, pale or bluish nasal mucosa, and possibly infraorbital cyanosis. Nasal, ocular, and/or palate irritation can be present as well.
Extensive rubbing of the nose over an extended period of time can also lead to a characteristic transverse nasal crease.
A positive intracutaneous skin test can provide proof of triggering allergens.
This condition is characterized by a Type I (IgE-mediated) acute hypersensitivity reaction to environmental allergens. Patients will often have a personal or family history of other atopic diseases such as asthma or atopic dermatitis. The syndrome is marked by a predisposition to produce IgE antibodies to environmental antigens. As these antigens are filtered by the nasal airways, interaction with surface-bound IgE antibodies on mast cells and basophils triggers a release of preformed mediators and the de novo synthesis of additional mediators, as well as the creation and release of proinflammatory cytokines. Interaction of mediators induces a complicated reaction in target organs, which includes the release of histamine and other stored mediators in the initiation of a complex cascade of actions. Frequent or persistent exposure leads to mucus hypersecretion, IgE production, eosinophilia, and tissue damage. Patients will most usually appear with congestion, clear nasal discharge, pale or bluish nasal mucosa, and possibly infraorbital cyanosis. Nasal, ocular, and/or palate irritation can be present as well.
Extensive rubbing of the nose over an extended period of time can also lead to a characteristic transverse nasal crease.
A positive intracutaneous skin test can provide proof of triggering allergens.
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Pathology - IgA Deficiency
IgA deficiency is a frequent genetic condition causing varying hypogammaglobulinemia. Patients may acquire a hypogammaglobulinemia at any age and may be asymptomatic. The condition develops when the respective immunoglobulin-producing B cells fail to mature into plasma cells. Patients have normal B cell numbers, but measurably reduced amounts of one particular kind of immunoglobulin. This instance depicts the classic symptomatic patient. Deficiency in secretory IgA (immunoglobulin A) at very low levels results in recurrent sinopulmonary and, most notably, Giardia infections. This patient is considerably dehydrated on physical examination, which can occur following considerable fluid loss from giardiasis. It is also important to recognize that anaphylaxis can occur if an IgAdeficient patient is exposed to blood products that contain IgA, which may be the first recognition of previously asymptomatic IgA-deficient adult. In addition, patients have elevated rates of allergy and autoimmune illnesses.
A similar presentation in an adult patient with decreased levels of numerous immunoglobulins (as opposed to a single immunoglobulin deficiency in IgA deficiency) is mixed variable immunodeficiency, from a failure in B-cell maturation to plasma cells.
IgA deficiency is a frequent genetic condition causing varying hypogammaglobulinemia. Patients may acquire a hypogammaglobulinemia at any age and may be asymptomatic. The condition develops when the respective immunoglobulin-producing B cells fail to mature into plasma cells. Patients have normal B cell numbers, but measurably reduced amounts of one particular kind of immunoglobulin. This instance depicts the classic symptomatic patient. Deficiency in secretory IgA (immunoglobulin A) at very low levels results in recurrent sinopulmonary and, most notably, Giardia infections. This patient is considerably dehydrated on physical examination, which can occur following considerable fluid loss from giardiasis. It is also important to recognize that anaphylaxis can occur if an IgAdeficient patient is exposed to blood products that contain IgA, which may be the first recognition of previously asymptomatic IgA-deficient adult. In addition, patients have elevated rates of allergy and autoimmune illnesses.
A similar presentation in an adult patient with decreased levels of numerous immunoglobulins (as opposed to a single immunoglobulin deficiency in IgA deficiency) is mixed variable immunodeficiency, from a failure in B-cell maturation to plasma cells.
