Immunology Flashcards
(260 cards)
1
Q
What is Severe Combined Immunodeficiency (SCID)?
A
SCID is a group of rare, life-threatening primary immunodeficiency disorders characterized by defective development of both T and B lymphocytes, resulting in severe impairment of cellular and humoral immunity.
2
Q
What are the two main immunological classifications of SCID?
A
SCID can be classified based on lymphocyte phenotype into:
1. T– B+ SCID (T cell deficiency with preserved B cells)
2. T– B– SCID (deficiency of both T and B cells)
3
Q
What is the most common genetic cause of SCID?
A
The most common cause is a mutation in the IL2RG gene (X-linked SCID), accounting for nearly 45% of cases.
4
Q
What are common clinical features of SCID?
A
Recurrent infections (bacterial, viral, fungal), persistent diarrhea, failure to thrive, chronic thrush, and absent lymphoid tissues (tonsils and lymph nodes).
5
Q
When should SCID be suspected in an infant?
A
SCID should be suspected in any infant with severe, recurrent infections, especially opportunistic infections, and who fails to thrive or has a positive family history of early infant deaths.
6
Q
What laboratory findings support the diagnosis of SCID?
A
Lymphopenia (especially CD3+ T cells), absent or low immunoglobulin levels, and lack of response to vaccines. Flow cytometry helps define T, B, and NK cell subsets.
7
Q
What is the role of newborn screening in SCID?
A
Newborn screening uses T-cell receptor excision circles (TRECs) to detect T-cell lymphopenia early, enabling timely diagnosis and treatment before infections occur.
8
Q
What is the definitive treatment for SCID?
A
Hematopoietic stem cell transplantation (HSCT) is the treatment of choice and is most effective when performed before 3.5 months of age.
9
Q
What are supportive treatments for SCID prior to HSCT?
A
Antimicrobial prophylaxis (e.g., TMP-SMX), IVIG replacement, isolation from infections, and avoiding live vaccines.
10
Q
What infections are SCID patients particularly vulnerable to?
A
Pneumocystis jirovecii pneumonia, CMV, rotavirus, Candida, and disseminated BCG (if vaccinated).
11
Q
What are the different genetic inheritance patterns of SCID?
A
SCID can be inherited in an X-linked pattern (e.g., IL2RG mutation) or autosomal recessive pattern (e.g., ADA deficiency, RAG1/RAG2 mutations).
12
Q
What is the pathophysiology of SCID due to IL2RG mutation?
A
IL2RG encodes the common gamma chain (γc) used by interleukin receptors (IL-2, IL-4, IL-7, IL-9, IL-15, IL-21); mutation leads to failure of T and NK cell development.
13
Q
What is ADA deficiency and how does it cause SCID?
A
Adenosine deaminase (ADA) deficiency causes accumulation of toxic metabolites (deoxyadenosine), which are toxic to lymphocytes, leading to SCID.
14
Q
How does RAG1/RAG2 mutation contribute to SCID?
A
RAG1 and RAG2 genes are essential for V(D)J recombination in T and B cell receptors. Mutations result in T– B– NK+ SCID phenotype.
15
Q
What is Omenn syndrome and how is it related to SCID?
A
Omenn syndrome is a variant of SCID caused by hypomorphic mutations in RAG genes, presenting with erythroderma, lymphadenopathy, eosinophilia, and elevated IgE.
16
Q
What are the typical findings on chest X-ray in SCID?
A
Absent or severely reduced thymic shadow due to thymic hypoplasia or aplasia.
17
Q
Why should live vaccines be avoided in SCID?
A
Live vaccines (e.g., BCG, MMR, rotavirus) can cause severe, disseminated infections in immunodeficient patients.
18
Q
What are the findings on flow cytometry in SCID?
A
Reduced or absent CD3+ T cells, variable B (CD19+) and NK (CD16+/CD56+) cells, depending on the genetic subtype.
19
Q
How does SCID increase the risk of graft-versus-host disease (GVHD)?
A
Maternal T cells can engraft in the infant (due to immune incompetence), leading to GVHD with rash, hepatosplenomegaly, and diarrhea.
20
Q
What is the prognosis of SCID without treatment?
A
Without treatment, SCID is fatal within the first year of life due to overwhelming infections.
21
Q
What is the role of IVIG in the management of SCID?
A
Intravenous immunoglobulin (IVIG) provides passive immunity to reduce infection risk until definitive treatment like HSCT is done.
22
Q
Why is early diagnosis crucial in SCID?
A
Early diagnosis allows for curative HSCT before the onset of severe infections, significantly improving survival rates.
23
Q
What is the role of gene therapy in SCID?
A
Gene therapy is an emerging treatment, especially for ADA-deficient SCID and X-linked SCID, where corrected genes are introduced into the patient’s own hematopoietic stem cells.
24
Q
What is the typical age of presentation for SCID?
A
SCID usually presents within the first 3 to 6 months of life with infections, diarrhea, and failure to thrive.
25
What is the significance of NK cell phenotype in SCID classification?
NK cell presence helps subclassify SCID and can guide the underlying genetic defect (e.g., IL2RG deficiency causes T– B+ NK–).
26
Which SCID subtype is associated with purine nucleoside phosphorylase (PNP) deficiency?
PNP deficiency SCID presents with T– B+ NK+ phenotype and is associated with neurologic symptoms like developmental delay.
27
How does JAK3 mutation cause SCID?
JAK3 mutations disrupt signaling through the common gamma chain receptor, leading to T– B+ NK– SCID, similar to IL2RG mutation.
28
What is leaky SCID?
Leaky SCID refers to a milder phenotype of SCID where some T cell function is retained, often due to hypomorphic mutations.
29
What non-infectious complications may occur in SCID?
Autoimmunity, GVHD from maternal T cells, and eosinophilic inflammation in Omenn syndrome.
30
What infections are most commonly seen in ADA-deficient SCID?
Pneumocystis jirovecii pneumonia, chronic viral infections, candidiasis, and bacterial sepsis.
31
What is DiGeorge syndrome?
DiGeorge syndrome is a primary immunodeficiency disorder caused by a deletion on chromosome 22q11.2, leading to abnormal development of the third and fourth pharyngeal pouches, resulting in thymic hypoplasia, hypocalcemia, and cardiac defects.
32
What embryologic structures are affected in DiGeorge syndrome?
The third and fourth pharyngeal pouches, which give rise to the thymus, parathyroid glands, and parts of the heart.
33
What are the classic clinical triad features of DiGeorge syndrome?
1. Congenital heart defects (especially conotruncal anomalies)
2. Hypocalcemia due to hypoparathyroidism
3. T-cell immunodeficiency from thymic hypoplasia
34
What cardiac anomalies are commonly seen in DiGeorge syndrome?
Tetralogy of Fallot, truncus arteriosus, interrupted aortic arch, and ventricular septal defects.
35
How does DiGeorge syndrome cause immunodeficiency?
Thymic hypoplasia or aplasia impairs T-cell development, leading to varying degrees of cellular immunodeficiency.
36
What are common facial features seen in DiGeorge syndrome?
Low-set ears, hypertelorism, short philtrum, micrognathia, and cleft palate or velopharyngeal insufficiency.
37
What metabolic abnormality is often found in infants with DiGeorge syndrome?
Hypocalcemia due to absent or underdeveloped parathyroid glands.
38
How is the diagnosis of DiGeorge syndrome confirmed?
By detecting a 22q11.2 microdeletion using FISH (fluorescence in situ hybridization) or chromosomal microarray.
39
What infections are DiGeorge patients susceptible to?
Recurrent viral, fungal, and opportunistic infections due to impaired T-cell function.
40
What is the immunologic phenotype in DiGeorge syndrome?
Variable T-cell lymphopenia depending on the degree of thymic hypoplasia; B-cell numbers are usually normal but antibody response may be impaired.
41
What neurological and psychiatric conditions are associated with DiGeorge syndrome?
Increased risk of developmental delay, intellectual disability, ADHD, autism spectrum disorder, and schizophrenia.
42
What are the common palatal abnormalities in DiGeorge syndrome?
Cleft palate, submucosal cleft palate, and velopharyngeal insufficiency leading to nasal speech.
43
How is calcium monitored and managed in DiGeorge syndrome?
Frequent monitoring of serum calcium; treatment includes oral calcium and active vitamin D analogs like calcitriol.
44
What are the hematologic findings in DiGeorge syndrome?
Lymphopenia due to T-cell deficiency; neutropenia may be seen with autoimmune cytopenias.
45
What role does thymic transplantation play in DiGeorge syndrome?
In complete DiGeorge syndrome with absent thymus, thymic transplantation can restore T-cell immunity.
46
How does DiGeorge syndrome affect the immune response to vaccines?
T-cell dependent responses may be impaired; live vaccines are avoided in patients with severe T-cell deficiency.
47
What endocrine problems may occur in DiGeorge syndrome?
Hypoparathyroidism (causing hypocalcemia), and rarely, growth hormone deficiency or thyroid disorders.
48
What renal anomalies are associated with DiGeorge syndrome?
Renal agenesis, hydronephrosis, and structural anomalies are common and require ultrasound screening.
49
What gastrointestinal problems can be seen in DiGeorge syndrome?
Feeding difficulties, gastroesophageal reflux, and malrotation may occur.
50
What are the reproductive implications for individuals with DiGeorge syndrome?
While fertility may be normal, genetic counseling is essential due to 50% risk of transmission if 22q11.2 deletion is present.
51
What are the types of DiGeorge syndrome based on thymic development?
Partial DiGeorge syndrome (hypoplastic thymus with some T-cell function) and complete DiGeorge syndrome (absent thymus with profound T-cell deficiency).
52
What is the difference between DiGeorge syndrome and CHARGE syndrome?
CHARGE syndrome includes coloboma, heart defects, choanal atresia, growth retardation, genital anomalies, and ear abnormalities, and lacks the consistent 22q11.2 deletion seen in DiGeorge.
53
How does 22q11.2 deletion affect craniofacial development?
It disrupts neural crest migration, leading to facial dysmorphism such as cleft palate, micrognathia, and low-set ears.
54
What are some psychiatric disorders more prevalent in adolescents and adults with DiGeorge syndrome?
Anxiety, depression, bipolar disorder, and a significantly increased risk of schizophrenia.
55
How is growth monitored in children with DiGeorge syndrome?
Regular growth assessments are necessary, especially due to feeding difficulties, endocrinopathies, and genetic factors.
56
What is the importance of genetic counseling in DiGeorge syndrome?
It informs families about recurrence risk, inheritance pattern (autosomal dominant), and guides prenatal or preimplantation diagnosis.
57
What prenatal findings might suggest DiGeorge syndrome?
Conotruncal cardiac defects, polyhydramnios, and thymic hypoplasia on fetal ultrasound.
58
How are speech and learning difficulties managed in DiGeorge syndrome?
Speech therapy, individualized education plans (IEPs), and neurodevelopmental assessments are crucial.
59
What type of hearing problems can occur in DiGeorge syndrome?
Conductive hearing loss due to otitis media with effusion and less commonly sensorineural hearing loss.
60
How often should immune function be re-evaluated in DiGeorge syndrome?
Annually or more frequently in infancy to monitor T-cell function and vaccine responses.
61
What is Wiskott-Aldrich syndrome (WAS)?
WAS is a rare X-linked recessive primary immunodeficiency characterized by a triad of eczema, thrombocytopenia with small platelets, and combined T- and B-cell immunodeficiency.
62
What is the genetic basis of Wiskott-Aldrich syndrome?
Mutations in the WAS gene on the X chromosome, which encodes the WAS protein (WASP), essential for actin cytoskeleton remodeling in immune cells.
63
What is the typical immunologic phenotype in WAS?
Low IgM, elevated IgA and IgE, normal to reduced IgG, defective T-cell function, and impaired antibody response to polysaccharide antigens.
64
What are the hematologic findings in WAS?
Thrombocytopenia with small-sized platelets (mean platelet volume is decreased), often leading to petechiae, epistaxis, and bleeding.
65
What are the common infections in patients with WAS?
Recurrent otitis media, pneumonia, skin infections, and opportunistic infections due to combined immunodeficiency.
66
What autoimmune complications are associated with WAS?
Autoimmune hemolytic anemia, vasculitis, arthritis, and inflammatory bowel disease.
67
What is the risk of malignancy in WAS?
Increased risk of lymphomas, particularly Epstein-Barr virus (EBV)-associated B-cell lymphomas.
68
How is the diagnosis of WAS confirmed?
By identifying a mutation in the WAS gene through genetic testing and evaluating WASP expression using flow cytometry.
69
What is the definitive treatment for Wiskott-Aldrich syndrome?
Hematopoietic stem cell transplantation (HSCT) is the only curative treatment, ideally performed early in life.
70
What supportive treatments are used in WAS?
IVIG, platelet transfusions (if bleeding), prophylactic antibiotics, avoidance of live vaccines, and management of eczema.
71
What laboratory finding helps differentiate WAS from other thrombocytopenias?
WAS typically presents with a low mean platelet volume (MPV), which distinguishes it from other causes of thrombocytopenia where platelets are normal or large.
72
How does eczema in WAS typically present?
Eczema in WAS often resembles atopic dermatitis, beginning in infancy and frequently complicated by secondary infections.
73
What is X-linked thrombocytopenia (XLT), and how is it related to WAS?
XLT is a milder allelic variant of WAS caused by hypomorphic mutations, presenting mainly with thrombocytopenia and minimal immune deficiency.
74
How does WAS affect T-cell function?
WASP deficiency impairs T-cell receptor signaling, cytoskeletal rearrangement, and T-cell activation, leading to increased susceptibility to infections.
75
What role does WASP protein play in immune cell function?
WASP regulates actin cytoskeleton remodeling, which is critical for immune synapse formation, cell migration, and phagocytosis.
76
How does B-cell function change in WAS?
B-cell numbers may be normal but antibody responses are impaired, particularly to polysaccharide antigens due to T-cell help deficiency.
77
What are common dermatologic complications in WAS?
Persistent eczema, secondary bacterial infections, and bleeding into the skin due to thrombocytopenia.
78
What is the long-term prognosis of untreated WAS?
Without HSCT, patients have reduced life expectancy due to infections, bleeding, and malignancies, often dying in early childhood.
79
What are current gene therapy approaches for WAS?
Gene therapy involves introducing functional WASP gene into autologous hematopoietic stem cells and has shown promise in clinical trials.
80
When should HSCT ideally be performed in WAS?
HSCT should be performed as early as possible before severe infections or malignancies develop, preferably within the first few years of life.
81
What is Ataxia-Telangiectasia (A-T)?
A-T is a rare, autosomal recessive primary immunodeficiency and neurodegenerative disorder caused by mutations in the ATM gene, leading to progressive cerebellar ataxia, telangiectasias, and immunodeficiency.
82
What gene is mutated in Ataxia-Telangiectasia, and what is its function?
The ATM (ataxia telangiectasia mutated) gene, which encodes a protein kinase involved in DNA double-strand break repair and cell cycle regulation.
83
What are the hallmark clinical features of Ataxia-Telangiectasia?
Progressive cerebellar ataxia, oculocutaneous telangiectasias (especially conjunctiva), recurrent sinopulmonary infections, and increased cancer risk.
84
When do symptoms of Ataxia-Telangiectasia typically begin?
Symptoms usually begin between 1 and 4 years of age, with progressive gait ataxia as the first sign.
85
What immunodeficiency is associated with Ataxia-Telangiectasia?
Combined immunodeficiency—low IgA, IgG2, and IgE; normal or elevated IgM; and reduced T-cell function.
86
What are telangiectasias and where are they typically seen in A-T?
Dilated capillaries (telangiectasias), most commonly seen in the bulbar conjunctiva and sometimes on the ears, face, and neck.
87
Why are patients with Ataxia-Telangiectasia at increased cancer risk?
Due to defective DNA repair mechanisms, they are predisposed to lymphoid malignancies (e.g., leukemias, lymphomas).
88
How is the diagnosis of Ataxia-Telangiectasia confirmed?
Clinical features plus elevated alpha-fetoprotein (AFP) levels and confirmed by ATM gene mutation analysis.
89
What are neurologic findings seen in Ataxia-Telangiectasia?
Progressive cerebellar ataxia, dysarthria, oculomotor apraxia, choreoathetosis, and peripheral neuropathy.
90
What type of radiation sensitivity is characteristic of A-T?
Marked hypersensitivity to ionizing radiation, due to impaired DNA repair mechanisms.
91
What is the typical pattern of serum alpha-fetoprotein (AFP) in Ataxia-Telangiectasia?
AFP is typically elevated in patients with A-T and serves as a useful diagnostic biomarker.
92
What are common pulmonary complications in Ataxia-Telangiectasia?
Recurrent respiratory infections, bronchiectasis, and interstitial lung disease due to immunodeficiency and neuromuscular weakness.
93
Why should radiation and radiomimetic drugs be avoided in A-T?
Patients have increased sensitivity to DNA damage and are at high risk for severe side effects and malignancies.
94
How does Ataxia-Telangiectasia affect the eyes?
Oculomotor apraxia (difficulty initiating eye movements), telangiectasias of the conjunctiva, and possible nystagmus.
95
What are the key differences between A-T and other cerebellar ataxias?
A-T is associated with immunodeficiency, telangiectasias, elevated AFP, and radiosensitivity—features not seen in most other ataxias.
96
What types of malignancies are most commonly seen in A-T?
Non-Hodgkin lymphomas and acute lymphoblastic leukemia (ALL) are the most common cancers.
97
How does A-T affect cognitive function?
Cognition is often preserved initially, but progressive neurologic decline may affect motor skills, coordination, and eventually cognition.
98
Is immunoglobulin replacement therapy used in A-T?
Yes, IVIG may be used in patients with significant antibody deficiency and recurrent infections.
99
What is the inheritance pattern of Ataxia-Telangiectasia?
Autosomal recessive; both parents are typically asymptomatic carriers.
100
What is the life expectancy of patients with A-T?
Life expectancy is reduced, often into the second or third decade, depending on severity and complications such as malignancy or lung disease.
101
What is Hyper IgE Syndrome (HIES)?
HIES is a rare primary immunodeficiency characterized by extremely elevated IgE levels, recurrent skin and lung infections, eczema-like dermatitis, and connective tissue and skeletal abnormalities.
102
What are the two major forms of Hyper IgE Syndrome?
1. Autosomal dominant HIES (Job syndrome) – due to STAT3 mutations
2. Autosomal recessive HIES – associated with DOCK8 or TYK2 mutations
103
What is the genetic mutation in autosomal dominant HIES?
Mutation in the STAT3 gene, which disrupts Th17 cell differentiation and impairs host defense against fungi and bacteria.
104
What are the hallmark clinical features of autosomal dominant HIES?
Eczema, recurrent staphylococcal skin abscesses, pneumonia with pneumatocele formation, retained primary teeth, scoliosis, and characteristic facies.
105
What infections are common in Hyper IgE Syndrome?
Recurrent skin abscesses (often 'cold' without inflammation), pneumonias (especially with Staph aureus), mucocutaneous candidiasis, and viral skin infections.
106
What are characteristic facial features in STAT3-HIES?
Broad nasal bridge, prominent forehead, deep-set eyes, and coarse facial features.
107
How does DOCK8-deficient (AR) HIES differ from STAT3-HIES?
DOCK8-HIES lacks skeletal/connective tissue features but has severe viral infections, allergies, autoimmunity, and increased malignancy risk.
108
What immunologic findings are seen in HIES?
Markedly elevated serum IgE, eosinophilia, and reduced Th17 cell numbers (especially in STAT3-HIES).
109
What is the role of Th17 cells in HIES pathophysiology?
Th17 cells are crucial for neutrophil recruitment and mucosal defense; deficiency (in STAT3 mutations) leads to fungal and bacterial susceptibility.
110
What is the definitive treatment for DOCK8-deficient HIES?
Hematopoietic stem cell transplantation (HSCT) is the only curative option for autosomal recessive DOCK8-deficient HIES.
111
What dental finding is characteristic of Hyper IgE Syndrome?
Retention of primary teeth leading to delayed eruption of permanent teeth.
112
What skeletal abnormalities are seen in STAT3-HIES?
Scoliosis, pathological fractures, joint hyperextensibility, and craniosynostosis.
113
What is the typical IgE level in Hyper IgE Syndrome?
Serum IgE levels are usually >2000 IU/mL, often >10,000 IU/mL.
114
What distinguishes STAT3-HIES from atopic dermatitis?
Cold abscesses without inflammation, skeletal anomalies, and lack of allergic sensitization in STAT3-HIES.
115
What malignancies are associated with DOCK8-deficient HIES?
Increased risk of squamous cell carcinoma and hematologic malignancies such as lymphoma.
116
What neurologic symptoms may occur in DOCK8-HIES?
Peripheral neuropathy, neurodevelopmental delay, and progressive cognitive decline in severe cases.
117
What is the role of prophylactic antibiotics in HIES?
Used to prevent recurrent bacterial and fungal infections, especially in patients awaiting definitive therapy.
118
Can patients with STAT3-HIES undergo HSCT?
HSCT is not typically curative for STAT3-HIES, as it does not correct non-immune features like skeletal and dental anomalies.
119
What allergic manifestations are common in DOCK8-HIES?
Food allergies, asthma, eosinophilic esophagitis, and eczema.
120
What is the long-term prognosis of Hyper IgE Syndrome?
Prognosis depends on type: DOCK8-HIES has higher mortality from infections and malignancies; STAT3-HIES patients may live into adulthood with supportive care.
121
What is Selective IgA Deficiency?
It is a primary immunodeficiency characterized by a marked decrease or absence of serum and secretory IgA with normal levels of other immunoglobulins (IgG and IgM), in individuals over 4 years of age.
122
What is the typical serum IgA level in Selective IgA Deficiency?
Serum IgA level is <7 mg/dL in the presence of normal IgG and IgM.
123
What is the most common clinical presentation of Selective IgA Deficiency?
Many patients are asymptomatic, but symptomatic individuals may present with recurrent respiratory and gastrointestinal infections.
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What autoimmune diseases are associated with Selective IgA Deficiency?
Celiac disease, systemic lupus erythematosus (SLE), rheumatoid arthritis, and autoimmune thyroiditis.
125
What allergic conditions are common in Selective IgA Deficiency?
Asthma, eczema, and allergic rhinitis are frequently observed.
126
Why is Selective IgA Deficiency important in blood transfusion medicine?
Patients may develop anti-IgA antibodies, which can cause anaphylactic reactions during transfusion of IgA-containing blood products.
127
How is Selective IgA Deficiency diagnosed?
By measuring serum immunoglobulins, confirming low IgA (<7 mg/dL) with normal IgG and IgM, in patients older than 4 years, and excluding other causes.
128
What is the management of Selective IgA Deficiency?
Supportive care, prompt treatment of infections, avoidance of blood products with IgA if anti-IgA antibodies are present, and management of associated conditions.
129
Can patients with Selective IgA Deficiency receive IVIG therapy?
IVIG is not routinely used since standard preparations contain very low IgA; it's only considered in cases with associated IgG subclass deficiency and recurrent infections.
130
What is the long-term prognosis for patients with Selective IgA Deficiency?
Generally good, especially for asymptomatic individuals, but increased risk of infections, autoimmunity, and progression to common variable immunodeficiency (CVID) in some.
131
What gastrointestinal disorders are commonly associated with Selective IgA Deficiency?
Giardiasis, chronic diarrhea, celiac disease, and inflammatory bowel disease.
132
Why are mucosal infections more common in IgA deficiency?
IgA is the primary immunoglobulin in mucosal secretions; its absence impairs defense against respiratory and gastrointestinal pathogens.
133
Can IgA Deficiency be detected in infants?
No, because serum IgA levels are naturally low in infancy. Diagnosis is only made after age 4.
134
What is the significance of anti-IgA antibodies in IgA Deficiency?
They can cause severe anaphylactic reactions to blood products containing IgA.
135
Is Selective IgA Deficiency inherited?
Yes, it can have a familial pattern and may be inherited as an autosomal dominant or recessive trait.
136
What laboratory tests are recommended to confirm IgA deficiency?
Quantitative serum immunoglobulins (IgA, IgG, IgM) and measurement of IgG subclasses if recurrent infections are present.
137
What is the relationship between IgA Deficiency and Common Variable Immunodeficiency (CVID)?
A subset of patients with IgA deficiency may progress to CVID later in life, especially if IgG subclasses are also low.
138
What are some vaccines to be cautious with in IgA Deficiency?
Live vaccines are generally safe, but caution is needed in patients with additional immunodeficiencies or poor responses.
139
What is the role of genetic testing in IgA Deficiency?
Genetic testing is not routinely required but may help in familial cases or when associated with syndromic features.
140
Can IgA Deficiency be associated with malignancy?
There is a slightly increased risk of gastrointestinal lymphomas and autoimmune-associated malignancies.
141
What is Common Variable Immunodeficiency (CVID)?
CVID is a heterogeneous primary immunodeficiency characterized by hypogammaglobulinemia (especially IgG and IgA, sometimes IgM), impaired antibody responses, and increased susceptibility to infections, autoimmunity, and malignancies.
142
At what age does CVID typically present?
CVID can present at any age, but most commonly between ages 15 and 35, though pediatric cases also occur.
143
What are the hallmark immunologic abnormalities in CVID?
Low serum IgG, low IgA and/or IgM, poor or absent response to vaccines, and impaired memory B-cell differentiation.
144
What types of infections are common in CVID?
Recurrent sinopulmonary infections, especially with Streptococcus pneumoniae and Haemophilus influenzae, and chronic gastrointestinal infections (e.g., Giardia, norovirus).
145
What autoimmune disorders are associated with CVID?
Autoimmune cytopenias (ITP, AIHA), rheumatoid arthritis, autoimmune thyroiditis, and inflammatory bowel disease-like colitis.
146
What non-infectious complications are common in CVID?
Granulomatous disease, lymphadenopathy, splenomegaly, interstitial lung disease, and enteropathy.
147
What malignancies are more common in CVID patients?
Non-Hodgkin lymphoma and gastric carcinoma are significantly increased.
148
How is CVID diagnosed?
By demonstrating:
1. Low IgG and low IgA and/or IgM
2. Poor vaccine response
3. Exclusion of other causes of hypogammaglobulinemia
149
What is the cornerstone of treatment for CVID?
Lifelong immunoglobulin replacement therapy (IVIG or SCIG) to prevent infections and complications.
150
What vaccine considerations exist for patients with CVID?
Live vaccines are contraindicated, and inactivated vaccines may have poor efficacy due to defective antibody production.
151
What is the role of B-cell phenotyping in CVID?
Flow cytometry can reveal decreased switched memory B cells and increased CD21^low B cells, which correlate with severity and complications.
152
How is interstitial lung disease (ILD) in CVID managed?
Management includes immunoglobulin therapy, corticosteroids, and immunosuppressants; early recognition via CT scan and pulmonary function tests is important.
153
What gastrointestinal manifestations are seen in CVID?
Chronic diarrhea, malabsorption, nodular lymphoid hyperplasia, villous atrophy, and IBD-like colitis.
154
What is the typical histology of CVID-associated enteropathy?
Villous blunting, increased intraepithelial lymphocytes, and lymphoid hyperplasia—can resemble celiac disease.
155
How are autoimmune cytopenias treated in CVID?
Steroids are first-line; other options include IVIG, rituximab, and immunosuppressive agents.
156
Why should CVID patients be monitored for malignancies?
They have increased risk of lymphomas and gastric cancer, especially with chronic inflammation and nodular lymphoid hyperplasia.
157
What is the risk of CVID progression in asymptomatic hypogammaglobulinemia?
Some asymptomatic individuals with low IgG may evolve into symptomatic CVID over time and require monitoring.
158
What syndromes or genes may overlap with CVID phenotype?
Mutations in ICOS, TACI (TNFRSF13B), CD19, CD20, CD21, and LRBA may present with CVID-like phenotype.
159
What is the role of regular monitoring in CVID patients?
Includes CBC, liver enzymes, lung function, imaging, and GI assessment to detect complications early.
160
How is SCIG different from IVIG in CVID management?
SCIG offers better steady-state IgG levels, fewer systemic side effects, and can be self-administered at home.
161
What is X-linked Agammaglobulinemia (XLA)?
XLA is a primary immunodeficiency caused by a mutation in the BTK gene, leading to an arrest in B-cell development and profoundly low levels of all immunoglobulin isotypes.
162
What is the inheritance pattern of XLA?
X-linked recessive, primarily affecting males.
163
What is the role of BTK (Bruton Tyrosine Kinase) in B-cell development?
BTK is essential for B-cell maturation beyond the pre-B cell stage in the bone marrow. Mutation causes B-cell developmental arrest.
164
What is the typical age of onset and presentation in XLA?
Infants appear healthy initially due to maternal IgG, but develop recurrent infections after 6 months of age, especially with encapsulated bacteria.
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What infections are common in XLA?
Recurrent otitis media, sinusitis, pneumonia, and infections with Streptococcus pneumoniae, Haemophilus influenzae, and enteroviruses.
166
What are the hallmark laboratory findings in XLA?
Profound hypogammaglobulinemia (low IgG, IgA, IgM), absent or severely reduced CD19+ B cells, and poor or absent vaccine response.
167
How is the diagnosis of XLA confirmed?
Based on clinical presentation, flow cytometry showing absent B cells, and genetic testing for BTK mutation.
168
What is seen on lymphoid tissue examination in XLA?
Absence or hypoplasia of tonsils, adenoids, lymph nodes, and Peyer’s patches due to lack of B cells.
169
What is the mainstay of treatment for XLA?
Lifelong IVIG or SCIG replacement therapy to prevent infections.
170
Are live vaccines safe in XLA?
No, live vaccines (e.g., MMR, oral polio, BCG) are contraindicated due to risk of disseminated infection.
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Why do enteroviral infections pose a serious risk in XLA?
Due to lack of neutralizing antibodies, patients with XLA are at increased risk of chronic meningoencephalitis caused by echovirus and poliovirus.
172
How are live virus infections in XLA patients diagnosed?
PCR or viral cultures from CSF or other sterile sites should be used; antibody-based tests are often negative due to humoral deficiency.
173
Can XLA patients develop autoimmune diseases?
Yes, although less common than in CVID, some XLA patients may develop arthritis or cytopenias.
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How is Ig replacement therapy monitored in XLA?
Regular IgG trough levels are monitored, aiming for levels >500–800 mg/dL and individualized based on infection frequency.
175
Why is early diagnosis of XLA important?
Early diagnosis allows prompt initiation of Ig therapy, reducing long-term complications like bronchiectasis and chronic infections.
176
How is family screening conducted for XLA?
Carrier testing and genetic counseling for female relatives, and early flow cytometry/genetic testing for male siblings.
177
What radiologic findings may be seen in XLA?
Chest X-rays may show chronic changes like bronchiectasis in untreated cases with recurrent pneumonia.
178
How does XLA differ from CVID?
XLA has an earlier onset, complete absence of B cells, BTK mutations, and absent Ig levels; CVID has variable B-cell function and later onset.
179
Can patients with XLA receive antibiotics?
Yes, they require prompt antibiotic treatment for infections, and some may benefit from prophylactic antibiotics.
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What is the prognosis for XLA with proper treatment?
With early diagnosis and lifelong Ig therapy, patients can live into adulthood with significantly reduced infection-related morbidity.
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What is Transient Hypogammaglobulinemia of Infancy (THI)?
THI is a self-limited delay in normal immunoglobulin (especially IgG) production in infants, resulting in temporarily increased susceptibility to infections.
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At what age does THI typically present?
Around 3 to 6 months of age, when maternal IgG levels decline and the infant's endogenous production is still low.
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What immunoglobulin levels are typically affected in THI?
Primarily low IgG, with normal or slightly low IgA and IgM.
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How is THI differentiated from XLA or CVID?
Unlike XLA/CVID, B cells are present in THI, vaccine responses are usually normal or mildly reduced, and IgG levels normalize by 2–4 years of age.
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What is the typical clinical presentation of THI?
Recurrent upper respiratory tract infections (e.g., otitis media, sinusitis), but usually milder than those seen in more severe immunodeficiencies.
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What is the long-term prognosis of THI?
Excellent—most children recover normal IgG levels by age 2–4 and do not develop chronic immune deficiency.
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What diagnostic tests support the diagnosis of THI?
Quantitative serum immunoglobulin levels and flow cytometry showing normal B cell numbers; diagnosis is retrospective after normalization of IgG.
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Is genetic testing required in THI?
No, THI is a diagnosis of exclusion and typically does not require genetic testing.
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What is the role of immunoglobulin replacement therapy in THI?
Usually not needed; may be considered temporarily in children with severe or frequent infections.
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How are children with THI managed?
Supportive care, monitoring IgG levels every 6–12 months, prompt treatment of infections, and avoiding unnecessary antibiotics or vaccines if immunoglobulins are very low.
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What is IgG Subclass Deficiency?
A primary immunodeficiency characterized by a deficiency in one or more of the IgG subclasses (IgG1, IgG2, IgG3, IgG4), despite normal total IgG levels.
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What is the clinical significance of IgG subclass deficiencies?
These deficiencies may predispose individuals to recurrent respiratory tract infections, especially with encapsulated bacteria.
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Which IgG subclass deficiency is most commonly associated with infections?
IgG2 deficiency, particularly in children, is most commonly associated with recurrent sinopulmonary infections.
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What age group is most commonly affected by IgG subclass deficiency?
It is more commonly identified in school-aged children, but can also be seen in adults with unexplained recurrent infections.
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How is IgG subclass deficiency diagnosed?
By measuring serum levels of IgG1, IgG2, IgG3, and IgG4 and confirming a reduced response to protein or polysaccharide vaccines.
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What types of infections are common in IgG subclass deficiency?
Recurrent otitis media, sinusitis, bronchitis, and sometimes pneumonia—often caused by Streptococcus pneumoniae and Haemophilus influenzae.
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How is the vaccine response used in the diagnosis of IgG subclass deficiency?
Poor or absent response to pneumococcal polysaccharide vaccines supports the diagnosis.
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Can IgG subclass deficiencies occur in combination with other immunodeficiencies?
Yes, they may co-exist with Selective IgA Deficiency or CVID and may indicate a broader immune defect.
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What is the management approach to IgG subclass deficiency?
Observation for mild cases; for symptomatic cases, treatment includes prompt antibiotics and sometimes IVIG or SCIG therapy.
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What is the prognosis for IgG subclass deficiency?
Many children outgrow the deficiency with age, but some may progress to CVID, requiring long-term monitoring.
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What is Severe Congenital Neutropenia (SCN)?
SCN is a primary immunodeficiency characterized by marked neutropenia (ANC <500/mm³) from birth due to arrested myeloid development in the bone marrow.
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What is the most common genetic cause of SCN?
ELANE gene mutation (neutrophil elastase), which causes maturation arrest of myeloid cells at the promyelocyte stage.
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What is the typical age of presentation for SCN?
Infants typically present in the first few months of life with recurrent severe bacterial infections (e.g., omphalitis, pneumonia, skin abscesses).
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What are the common infections in SCN?
Recurrent infections caused by Staphylococcus aureus, Pseudomonas, E. coli, and other pyogenic bacteria.
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What are the key laboratory findings in SCN?
ANC persistently <500/mm³; Bone marrow shows maturation arrest at the promyelocyte stage; Normal or elevated monocytes and lymphocytes.
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How is the diagnosis of SCN confirmed?
Clinical history, persistent neutropenia, bone marrow biopsy, and genetic testing (e.g., ELANE, HAX1, G6PC3 mutations).
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What is the mainstay of treatment for SCN?
Daily G-CSF (filgrastim) injections to stimulate neutrophil production and prevent infections.
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What are potential complications of long-term SCN?
Increased risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), especially in patients on long-term G-CSF.
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What is the role of hematopoietic stem cell transplantation (HSCT) in SCN?
HSCT is curative and considered for G-CSF unresponsive patients or those with leukemic transformation.
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How is SCN distinguished from cyclic neutropenia?
SCN shows persistent neutropenia, whereas cyclic neutropenia has periodic drops in ANC (~every 21 days) and usually a milder clinical course.
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What is Chronic Granulomatous Disease (CGD)?
CGD is a primary immunodeficiency caused by defective NADPH oxidase in phagocytes, leading to impaired intracellular killing of catalase-positive organisms.
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What is the most common inheritance pattern of CGD?
X-linked recessive, due to mutations in the CYBB gene (gp91^phox); autosomal recessive forms also exist (e.g., p47^phox deficiency).
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What types of infections are common in CGD?
Recurrent infections with catalase-positive organisms, such as Staphylococcus aureus, Serratia, Burkholderia cepacia, Nocardia, and Aspergillus.
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What are common clinical features of CGD?
Recurrent skin abscesses, pneumonia, lymphadenitis, osteomyelitis, and granuloma formation causing obstruction (e.g., GI or GU tract).
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What is the hallmark immunological defect in CGD?
Defective respiratory burst in neutrophils and monocytes due to NADPH oxidase complex dysfunction.
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What diagnostic tests are used for CGD?
1. Dihydrorhodamine (DHR) flow cytometry – preferred test
2. Nitroblue tetrazolium (NBT) test – older screening test
3. Genetic testing for NADPH oxidase subunit mutations
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What is the role of interferon-gamma in CGD?
IFN-γ prophylaxis can reduce infection frequency by enhancing phagocyte function.
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What is the mainstay of infection prevention in CGD?
Lifelong prophylactic antibiotics (e.g., trimethoprim-sulfamethoxazole) and antifungals (e.g., itraconazole).
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What is the curative treatment for CGD?
Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for CGD.
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What is the typical age and presentation of CGD?
Onset usually in early childhood with severe, recurrent infections and granulomatous inflammation.
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What is Leukocyte Adhesion Deficiency (LAD)?
LAD is a rare primary immunodeficiency characterized by defective leukocyte adhesion and migration, leading to impaired neutrophil trafficking and severe bacterial infections.
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What causes LAD Type 1?
LAD-1 is caused by mutations in the ITGB2 gene, resulting in absent or defective CD18, a key component of beta-2 integrins (LFA-1, Mac-1).
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What are hallmark clinical features of LAD-1?
Delayed umbilical cord separation (>30 days), recurrent bacterial infections without pus, poor wound healing, and marked leukocytosis with neutrophilia.
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What is the mechanism of infection in LAD?
Neutrophils cannot adhere to endothelial cells and migrate into tissues, leading to failure of recruitment to infection sites.
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What organisms commonly cause infections in LAD-1?
Gram-negative bacilli, Staphylococcus aureus, and Candida—typically involving skin, mucosa, and soft tissues.
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How is LAD-1 diagnosed?
Clinical presentation, flow cytometry showing absent or low CD18 expression, and genetic testing for ITGB2 mutation.
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What is LAD Type 2?
LAD-2 is caused by a defect in the fucosylation of selectin ligands due to SLC35C1 mutation, affecting rolling of leukocytes on endothelium.
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What additional features are seen in LAD-2?
In addition to infections, patients may have short stature, intellectual disability, and Bombay blood phenotype.
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What is the main treatment for LAD-1?
Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for severe LAD-1.
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What supportive treatments are used in LAD?
Aggressive antibiotic therapy, wound care, and G-CSF may be used to reduce infection frequency before HSCT.
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What is Chediak-Higashi Syndrome (CHS)?
CHS is a rare autosomal recessive disorder characterized by abnormal lysosomal trafficking, leading to recurrent infections, partial oculocutaneous albinism, and neurologic dysfunction.
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What gene is mutated in Chediak-Higashi Syndrome?
LYST gene (lysosomal trafficking regulator gene), responsible for proper lysosomal-vesicle fusion and trafficking in immune and pigment cells.
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What are the hallmark clinical features of CHS?
Partial albinism (light skin, silvery hair), recurrent pyogenic infections, peripheral neuropathy, and mild bleeding tendency.
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What is the life-threatening phase of CHS?
The accelerated phase—a hemophagocytic lymphohistiocytosis (HLH)-like condition with fever, pancytopenia, hepatosplenomegaly, and organ failure.
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What are the typical pathogens in CHS infections?
Staphylococcus aureus, Streptococcus pyogenes, and gram-negative bacteria.
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What is seen on peripheral blood smear in CHS?
Giant cytoplasmic granules in neutrophils, lymphocytes, and other granulocytes.
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What causes the bleeding tendency in CHS?
Platelet storage pool deficiency, resulting in defective dense granules and impaired platelet function.
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How is CHS diagnosed?
Clinical features, blood smear showing giant granules, and genetic testing for LYST mutations.
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What is the definitive treatment for CHS?
Hematopoietic stem cell transplantation (HSCT) is curative for the immunologic and hematologic features.
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What aspects of CHS are not corrected by HSCT?
Neurological symptoms and skin pigmentation defects are often progressive and not reversed by HSCT.
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What is Hyper IgM Syndrome?
A primary immunodeficiency characterized by normal or elevated IgM and low or absent IgG, IgA, and IgE due to defective class-switch recombination.
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What is the most common genetic cause of Hyper IgM Syndrome?
X-linked HIGM due to mutations in the CD40 ligand (CD40L) gene, affecting T-cell help for B-cell class switching.
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What are the main immunologic defects in Hyper IgM Syndrome?
Defective class-switch recombination, impaired T-cell-B-cell interaction, variable neutropenia, and defective macrophage activation.
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What types of infections are common in HIGM?
Recurrent sinopulmonary infections, Pneumocystis jirovecii pneumonia, cryptosporidial diarrhea, and liver abscesses.
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What is the typical immunoglobulin profile in HIGM?
Elevated or normal IgM, but low or absent IgG, IgA, and IgE.
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What are the clinical features of X-linked Hyper IgM Syndrome?
Recurrent bacterial infections, opportunistic infections (e.g., Pneumocystis), neutropenia, autoimmunity, and chronic diarrhea.
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How is HIGM diagnosed?
By measuring immunoglobulin levels, vaccine responses, flow cytometry for CD40L expression on activated T cells, and genetic testing.
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What are autosomal recessive causes of HIGM?
Mutations in AID, CD40, UNG, and others—typically causing more isolated B-cell defects and less severe opportunistic infections.
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What is the treatment of Hyper IgM Syndrome?
IVIG or SCIG replacement therapy, prophylactic antibiotics (e.g., TMP-SMX), and consideration for HSCT in severe cases.
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Why is cryptosporidial infection important in HIGM?
It can cause chronic diarrhea and sclerosing cholangitis, particularly in patients with CD40L deficiency, and is difficult to eradicate without immune reconstitution.
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What are complement deficiencies?
A group of primary immunodeficiencies caused by defects in one or more complement system proteins, impairing innate immunity and increasing susceptibility to infections or autoimmune disease.
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What infections are classically associated with terminal complement (C5–C9) deficiencies?
Recurrent Neisseria infections, especially Neisseria meningitidis and Neisseria gonorrhoeae.
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Which complement deficiencies are associated with autoimmune disease, especially lupus?
C1q, C2, and C4 deficiencies, particularly C1q, are strongly associated with systemic lupus erythematosus (SLE)-like syndromes.
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What is the clinical significance of C3 deficiency?
C3 deficiency results in severe recurrent pyogenic infections, impaired opsonization, and is associated with immune complex diseases.
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What are the classical, alternative, and lectin pathways of complement activation?
Classical: antibody-dependent (C1q, C2, C4); Alternative: spontaneous activation (Factor B, D, properdin); Lectin: mannose-binding lectin (MBL) pathway.
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What are symptoms of early classical pathway (C1–C4) deficiencies?
Recurrent sinopulmonary infections and increased risk of autoimmune disease (especially SLE).
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How is a complement deficiency diagnosed?
CH50 test for classical pathway, AH50 test for alternative pathway, and individual component assays to identify the specific deficiency.
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What is the role of properdin in complement function?
Properdin stabilizes the alternative pathway C3 convertase; its deficiency leads to increased risk of Neisseria infections.
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What are the risks associated with Mannose-Binding Lectin (MBL) deficiency?
MBL deficiency is common and usually mild but may cause recurrent infections in infants or immunocompromised patients.
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What is the treatment approach for complement deficiencies?
Vaccination against encapsulated organisms, prompt antibiotic treatment, and prophylactic antibiotics for high-risk patients.
