Podcast
Questions and Answers
What is the role of IL-12 secreted by macrophages in relation to CD4 + helper T cells?
What is the role of IL-12 secreted by macrophages in relation to CD4 + helper T cells?
- To induce differentiation into TH1 subtype (correct)
- To promote B cell maturation
- To convert macrophages to epithelioid histiocytes
- To directly kill pathogens
Which condition is primarily characterized by the developmental failure of the third and fourth pharyngeal pouches?
Which condition is primarily characterized by the developmental failure of the third and fourth pharyngeal pouches?
- Adenosine Deaminase Deficiency
- DiGeorge Syndrome (correct)
- Severe Combined Immunodeficiency (SCID)
- Cytokine Receptor Defect
What is a consequence of adenosine deaminase (ADA) deficiency?
What is a consequence of adenosine deaminase (ADA) deficiency?
- Overproduction of white blood cells
- Buildup of toxic metabolites leading to lymphocyte toxicity (correct)
- Increased T cell count due to lack of destruction
- Enhanced cytokine signaling
What is the primary immunodeficiency condition associated with T-cell deficiency and hypocalcemia?
What is the primary immunodeficiency condition associated with T-cell deficiency and hypocalcemia?
Which of the following is NOT a characteristic of Severe Combined Immunodeficiency (SCID)?
Which of the following is NOT a characteristic of Severe Combined Immunodeficiency (SCID)?
Which cells are converted to epithelioid histiocytes by the action of IFN-γ?
Which cells are converted to epithelioid histiocytes by the action of IFN-γ?
What genetic deletion is associated with DiGeorge Syndrome?
What genetic deletion is associated with DiGeorge Syndrome?
What kind of maturation is necessary for both B and T cells in the context of cytokine receptor defects?
What kind of maturation is necessary for both B and T cells in the context of cytokine receptor defects?
What genetic mutation is primarily associated with the autoimmune polyendocrine syndrome?
What genetic mutation is primarily associated with the autoimmune polyendocrine syndrome?
Which autoimmune disorder is characterized by the loss of self-tolerance in T cells, leading to widespread autoimmune reactions?
Which autoimmune disorder is characterized by the loss of self-tolerance in T cells, leading to widespread autoimmune reactions?
What is a consequence of deficiencies in the C5-C9 complement proteins?
What is a consequence of deficiencies in the C5-C9 complement proteins?
How does estrogen influence autoimmune disorders in women of childbearing age?
How does estrogen influence autoimmune disorders in women of childbearing age?
What is a common feature of autoimmune disorders regarding their prevalence?
What is a common feature of autoimmune disorders regarding their prevalence?
What is the primary cause of X-linked agammaglobulinemia?
What is the primary cause of X-linked agammaglobulinemia?
Which of the following infections are most commonly associated with common variable immunodeficiency (CVID)?
Which of the following infections are most commonly associated with common variable immunodeficiency (CVID)?
What is the most common immunoglobulin deficiency?
What is the most common immunoglobulin deficiency?
What characterizes Hyper-IgM syndrome?
What characterizes Hyper-IgM syndrome?
At what stage of life do symptoms of X-linked agammaglobulinemia typically present?
At what stage of life do symptoms of X-linked agammaglobulinemia typically present?
Which immunodeficiency is primarily associated with an increased risk for autoimmune disease and lymphoma?
Which immunodeficiency is primarily associated with an increased risk for autoimmune disease and lymphoma?
What is a significant consequence of IgA deficiency in patients?
What is a significant consequence of IgA deficiency in patients?
What type of infections should patients with X-linked agammaglobulinemia avoid?
What type of infections should patients with X-linked agammaglobulinemia avoid?
Thrombocytopenia, eczema, and recurrent infections are indicative of a condition related to a mutation in the WASP gene.
Thrombocytopenia, eczema, and recurrent infections are indicative of a condition related to a mutation in the WASP gene.
Complement deficiencies C5-C9 are primarily associated with an increased risk of infections caused by Streptococcus species.
Complement deficiencies C5-C9 are primarily associated with an increased risk of infections caused by Streptococcus species.
Immune-mediated damage of self tissues is not characteristic of autoimmune disorders.
Immune-mediated damage of self tissues is not characteristic of autoimmune disorders.
The presence of AIRE mutations can lead to autoimmune lymphoproliferative syndrome (ALPS).
The presence of AIRE mutations can lead to autoimmune lymphoproliferative syndrome (ALPS).
Regulatory T cells suppress autoimmunity by producing inflammatory cytokines such as IL-10.
Regulatory T cells suppress autoimmunity by producing inflammatory cytokines such as IL-10.
Macrophages present antigen via MHC class II to CD8 + cytotoxic T cells.
Macrophages present antigen via MHC class II to CD8 + cytotoxic T cells.
DiGeorge Syndrome is associated with a 22q11 microdeletion, leading to T-cell deficiency and hypocalcemia.
DiGeorge Syndrome is associated with a 22q11 microdeletion, leading to T-cell deficiency and hypocalcemia.
Severe Combined Immunodeficiency (SCID) only affects humoral immunity and has no effect on cell-mediated immunity.
Severe Combined Immunodeficiency (SCID) only affects humoral immunity and has no effect on cell-mediated immunity.
Adenosine deaminase (ADA) deficiency results in the accumulation of toxic metabolites that affect lymphocytes.
Adenosine deaminase (ADA) deficiency results in the accumulation of toxic metabolites that affect lymphocytes.
TH1 cells secrete IL-12, stimulating the differentiation of CD4 + helper T cells.
TH1 cells secrete IL-12, stimulating the differentiation of CD4 + helper T cells.
MHC class II deficiency impairs the activation and cytokine production of CD8 + cytotoxic T cells.
MHC class II deficiency impairs the activation and cytokine production of CD8 + cytotoxic T cells.
The lack of parathyroid glands in DiGeorge Syndrome can lead to hyposensitivity to calcium.
The lack of parathyroid glands in DiGeorge Syndrome can lead to hyposensitivity to calcium.
Macrophages transform into giant cells in response to IFN-γ stimulation.
Macrophages transform into giant cells in response to IFN-γ stimulation.
Patients with X-linked agammaglobulinemia are protected by maternal antibodies for the first 12 months of life.
Patients with X-linked agammaglobulinemia are protected by maternal antibodies for the first 12 months of life.
Common Variable Immunodeficiency (CVID) is characterized by an increased risk of granulomatous infections.
Common Variable Immunodeficiency (CVID) is characterized by an increased risk of granulomatous infections.
In Hyper-IgM syndrome, the defect lies in the ability of T cells to deliver a second signal to B cells during activation.
In Hyper-IgM syndrome, the defect lies in the ability of T cells to deliver a second signal to B cells during activation.
IgA deficiency is the rarest form of immunoglobulin deficiency.
IgA deficiency is the rarest form of immunoglobulin deficiency.
Patients with IgA deficiency typically experience a higher frequency of bacterial infections compared to viral infections.
Patients with IgA deficiency typically experience a higher frequency of bacterial infections compared to viral infections.
Bruton tyrosine kinase mutations are linked to the maturation failure of pre- and pro-B cells.
Bruton tyrosine kinase mutations are linked to the maturation failure of pre- and pro-B cells.
Wiskott-Aldrich Syndrome is primarily characterized by an elevation in IgG levels.
Wiskott-Aldrich Syndrome is primarily characterized by an elevation in IgG levels.
Maternal antibodies are ineffective against enteroviruses such as polio after the first 6 months in infants.
Maternal antibodies are ineffective against enteroviruses such as polio after the first 6 months in infants.
What are the primary clinical features of Wiskott-Aldrich Syndrome, and what genetic mutation is this condition associated with?
What are the primary clinical features of Wiskott-Aldrich Syndrome, and what genetic mutation is this condition associated with?
Explain the consequences of a C5-C9 complement deficiency and the type of infections it predisposes individuals to.
Explain the consequences of a C5-C9 complement deficiency and the type of infections it predisposes individuals to.
Discuss the role of regulatory T cells in maintaining self-tolerance and their relevance in autoimmune disorders.
Discuss the role of regulatory T cells in maintaining self-tolerance and their relevance in autoimmune disorders.
What is the significance of AIRE mutations in the context of autoimmune diseases?
What is the significance of AIRE mutations in the context of autoimmune diseases?
Outline the primary mechanisms leading to loss of self-tolerance in autoimmune disorders.
Outline the primary mechanisms leading to loss of self-tolerance in autoimmune disorders.
What is the significance of MHC class II in the context of T-cell activation by macrophages?
What is the significance of MHC class II in the context of T-cell activation by macrophages?
How does IL-12 influence the differentiation of CD4+ helper T cells in response to macrophage activity?
How does IL-12 influence the differentiation of CD4+ helper T cells in response to macrophage activity?
Describe the clinical manifestations associated with DiGeorge Syndrome.
Describe the clinical manifestations associated with DiGeorge Syndrome.
What role does adenosine deaminase (ADA) play in lymphocyte health?
What role does adenosine deaminase (ADA) play in lymphocyte health?
In what way does MHC class II deficiency impact immune function?
In what way does MHC class II deficiency impact immune function?
How does IFN-γ influence macrophage transformation in immune responses?
How does IFN-γ influence macrophage transformation in immune responses?
What are the consequences of cytokine receptor defects in terms of T and B cell maturation?
What are the consequences of cytokine receptor defects in terms of T and B cell maturation?
Explain the implications of the 22q11 microdeletion in DiGeorge Syndrome.
Explain the implications of the 22q11 microdeletion in DiGeorge Syndrome.
What mutation is responsible for the complete lack of immunoglobulin in X-linked agammaglobulinemia?
What mutation is responsible for the complete lack of immunoglobulin in X-linked agammaglobulinemia?
How does Hyper-IgM syndrome affect B-cell activation?
How does Hyper-IgM syndrome affect B-cell activation?
Which types of infections are individuals with Common Variable Immunodeficiency (CVID) particularly susceptible to?
Which types of infections are individuals with Common Variable Immunodeficiency (CVID) particularly susceptible to?
Why should patients with X-linked agammaglobulinemia avoid live vaccines?
Why should patients with X-linked agammaglobulinemia avoid live vaccines?
What is the most common immunoglobulin deficiency and what is its characteristic?
What is the most common immunoglobulin deficiency and what is its characteristic?
What consequence does low IgA, IgG, and IgE have in Hyper-IgM syndrome?
What consequence does low IgA, IgG, and IgE have in Hyper-IgM syndrome?
In Wiskott-Aldrich syndrome, what are the classic triad of symptoms?
In Wiskott-Aldrich syndrome, what are the classic triad of symptoms?
At what point in life do symptoms of X-linked agammaglobulinemia typically present, and why?
At what point in life do symptoms of X-linked agammaglobulinemia typically present, and why?
Wiskott-Aldrich Syndrome is characterized by thrombocytopenia, eczema, and recurrent ______.
Wiskott-Aldrich Syndrome is characterized by thrombocytopenia, eczema, and recurrent ______.
C5-C9 deficiencies are associated with an increased risk of ______ infections.
C5-C9 deficiencies are associated with an increased risk of ______ infections.
The loss of self-tolerance in autoimmune disorders involves self-reactive lymphocytes developing tolerance in the ______.
The loss of self-tolerance in autoimmune disorders involves self-reactive lymphocytes developing tolerance in the ______.
AIRE mutations can lead to autoimmune ______ syndrome.
AIRE mutations can lead to autoimmune ______ syndrome.
Regulatory T cells suppress autoimmunity by blocking T-cell activation and producing anti-inflammatory ______.
Regulatory T cells suppress autoimmunity by blocking T-cell activation and producing anti-inflammatory ______.
Macrophages present antigen via MHC class II to ______ cells.
Macrophages present antigen via MHC class II to ______ cells.
The 22q11 microdeletion is associated with ______ syndrome.
The 22q11 microdeletion is associated with ______ syndrome.
Adenosine deaminase (ADA) deficiency leads to the buildup of ______, which is toxic to lymphocytes.
Adenosine deaminase (ADA) deficiency leads to the buildup of ______, which is toxic to lymphocytes.
IFN-γ secreting TH1 cells convert macrophages to ______ histiocytes.
IFN-γ secreting TH1 cells convert macrophages to ______ histiocytes.
Severe Combined Immunodeficiency (SCID) results in defective ______-mediated and humoral immunity.
Severe Combined Immunodeficiency (SCID) results in defective ______-mediated and humoral immunity.
MHC class II is necessary for the activation of ______ T cells.
MHC class II is necessary for the activation of ______ T cells.
Patients with DiGeorge syndrome often present with ______ due to a lack of parathyroid glands.
Patients with DiGeorge syndrome often present with ______ due to a lack of parathyroid glands.
In Hyper-IgM syndrome, T cells fail to adequately deliver a second signal to ______ cells during activation.
In Hyper-IgM syndrome, T cells fail to adequately deliver a second signal to ______ cells during activation.
X-linked agammaglobulinemia is characterized by a complete lack of ______ due to disordered B-cell maturation.
X-linked agammaglobulinemia is characterized by a complete lack of ______ due to disordered B-cell maturation.
In common variable immunodeficiency (CVID), there is a low level of ______ due to B-cell or helper T-cell defects.
In common variable immunodeficiency (CVID), there is a low level of ______ due to B-cell or helper T-cell defects.
IgA deficiency is the most common type of ______ deficiency.
IgA deficiency is the most common type of ______ deficiency.
Hyper-IgM syndrome is characterized by elevated ______ levels due to a failure in B-cell activation.
Hyper-IgM syndrome is characterized by elevated ______ levels due to a failure in B-cell activation.
Patients with X-linked agammaglobulinemia must avoid live ______ as they are at high risk for infections.
Patients with X-linked agammaglobulinemia must avoid live ______ as they are at high risk for infections.
In the context of Hyper-IgM syndrome, the necessary cytokines for immunoglobulin ______ are not produced.
In the context of Hyper-IgM syndrome, the necessary cytokines for immunoglobulin ______ are not produced.
Wiskott-Aldrich syndrome is characterized by thrombocytopenia, eczema, and recurrent ______.
Wiskott-Aldrich syndrome is characterized by thrombocytopenia, eczema, and recurrent ______.
Patients with IgA deficiency are at an increased risk for ______ infections, particularly viral ones.
Patients with IgA deficiency are at an increased risk for ______ infections, particularly viral ones.
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Study Notes
Fundamentals of Pathology
- Macrophages process and present antigens to CD4+ helper T cells via MHC class II
- This interaction leads to IL-12 secretion by macrophages, which induces CD4+ helper T cells to differentiate into the TH1 subtype
- TH1 cells secrete IFN-γ, converting macrophages to epithelioid histiocytes and giant cells
Primary Immunodeficiency
-
DiGeorge Syndrome:
- Developmental failure of the third and fourth pharyngeal pouches
- Due to 22q11 microdeletion
- Presents with T-cell deficiency (lack of thymus), hypocalcemia (lack of parathyroids), and abnormalities of the heart, great vessels, and face
-
Severe Combined Immunodeficiency (SCID)
- Defective cell-mediated and humoral immunity
- Etiologies include:
- Cytokine receptor defects
- Adenosine deaminase (ADA) deficiency
- MHC class II deficiency
- Characterized by susceptibility to fungal, viral, bacterial, and protozoal infections, including opportunistic infections and live vaccines
- Treatment involves sterile isolation and stem cell transplantation
-
X-Linked Agammaglobulinemia
- Complete lack of immunoglobulin due to disordered B-cell maturation
- Pre- and pro-B cells cannot mature
- Due to mutated Bruton tyrosine kinase; X-linked
- Presents after 6 months of life with recurrent bacterial, enterovirus, and Giardia lamblia infections; maternal antibodies are protective during the first 6 months of life
- Live vaccines must be avoided
-
Common Variable Immunodeficiency (CVID)
- Low immunoglobulin due to B-cell or helper T-cell defects
- Increased risk for bacterial, enterovirus, and Giardia lamblia infections, usually in late childhood
- Increased risk for autoimmune disease and lymphoma
-
IgA Deficiency:
- Low serum and mucosal IgA; most common immunoglobulin deficiency
- Increased risk for mucosal infection, especially viral; however, most patients are asymptomatic
-
Hyper-IgM Syndrome:
- Characterized by elevated IgM
- Due to mutated CD40L (on helper T cells) or CD40 receptor (on B cells)
- Second signal cannot be delivered to helper T cells during B-cell activation
- Consequently, cytokines necessary for immunoglobulin class switching are not produced
- Low IgA, IgG, and IgE result in recurrent pyogenic infections (due to poor opsonization), especially at mucosal sites
-
Wiskott-Aldrich Syndrome:
- Characterized by thrombocytopenia, eczema, and recurrent infections (defective humoral and cellular immunity); bleeding is a major cause of death
- Due to mutation in the WASP gene; X-linked
-
Complement Deficiencies:
- C5-C9 deficiencies: increased risk for Neisseria infection (N gonorrhoeae and N meningitidis)
- Cl inhibitor deficiency: results in hereditary angioedema, characterized by edema of the skin (especially periorbital) and mucosal surfaces
Autoimmune Disorders
- Basic Principles:
- Characterized by immune-mediated damage of self tissues
- US prevalence is 1%-2%
- Involves loss of self-tolerance
- Self-reactive lymphocytes are regularly generated but develop central (thymus and bone marrow) or peripheral tolerance
- Central tolerance in the thymus leads to T-cell (thymocyte) apoptosis or generation of regulatory T cells
- Central tolerance in the bone marrow leads to receptor editing or B-cell apoptosis
- Peripheral tolerance leads to anergy or apoptosis of T and B cells
- Regulatory T cells suppress autoimmunity by blocking T-cell activation and producing anti-inflammatory cytokines (IL-10 and TGF-β)
- More common in women; classically affects women of childbearing age
- Etiology is likely an environmental trigger in genetically-susceptible individuals
- Increased incidence in twins
Fundamentals of Pathology
- Macrophages process and present antigens via MHC class II to CD4+ helper T cells.
- Macrophages secrete IL-12 after interacting with helper T cells.
- IL-12 causes helper T cells to differentiate into T H1 subtype.
- TH1 cells secrete IFN-γ, which converts macrophages into epithelioid histiocytes and giant cells.
Primary Immunodeficiency
-
DiGeorge Syndrome:
- Developmental failure of the third and fourth pharyngeal pouches.
- Caused by 22q11 microdeletion.
- Presents with T-cell deficiency, hypocalcemia, and abnormalities of the heart, great vessels, and face.
-
Severe Combined Immunodeficiency (SCID):
- Defective cell-mediated and humoral immunity.
- Etiologies involve:
- Cytokine receptor defects.
- Adenosine deaminase (ADA) deficiency.
- MHC class II deficiency.
- Characterized by susceptibility to fungal, viral, bacterial, and protozoal infections, including opportunistic infections and live vaccines.
- Treatment involves sterile isolation and stem cell transplantation.
-
X-Linked Agammaglobulinemia:
- Complete lack of immunoglobulin due to disordered B-cell maturation.
- Caused by a mutated Bruton tyrosine kinase, which is X-linked.
- Presents after six months of life with recurrent bacterial, enterovirus, and Giardia lamblia infections.
- Maternal antibodies present during the first six months of life provide protection.
- Live vaccines must be avoided.
-
Common Variable Immunodeficiency (CVID):
- Low immunoglobulin due to B-cell or helper T-cell defects.
- Increased risk of bacterial, enterovirus, and Giardia lamblia infections, usually in late childhood.
- Increased risk of autoimmune disease and lymphoma.
-
IgA Deficiency:
- Low serum and mucosal IgA, the most common immunoglobulin deficiency.
- Increased risk of mucosal infection, especially viral; however, most patients are asymptomatic.
-
Hyper-IgM Syndrome:
- Characterized by elevated IgM.
- Caused by a mutated CD40L (on helper T cells) or CD40 receptor (on B cells).
- Impaired delivery of the second signal to helper T cells during B-cell activation.
- Deficiency in IgA, IgG, and IgE, leading to recurrent pyogenic infections at mucosal sites.
-
Wiskott-Aldrich Syndrome:
- Characterized by thrombocytopenia, eczema, and recurrent infections (defective humoral and cellular immunity).
- Caused by a mutation in the WASP gene, which is X-linked.
- Bleeding is a major cause of death.
-
Complement Deficiencies:
- C5-C9 deficiencies increase the risk of Neisseria infection (N gonorrhoeae and N meningitidis).
- C1 inhibitor deficiency leads to hereditary angioedema, characterized by edema of the skin and mucosal surfaces.
Autoimmune Disorders
-
Basic Principles:
- Characterized by immune-mediated damage to self tissues.
- Involves loss of self-tolerance.
- More common in women, especially of childbearing age.
- Etiology likely involves an environmental trigger in genetically susceptible individuals.
-
Loss of Self-Tolerance:
- Self-reactive lymphocytes are regularly generated but become tolerant in the thymus or bone marrow.
- Central Tolerance:
- Central tolerance in the thymus leads to T-cell apoptosis or the generation of regulatory T cells.
- AIRE mutations result in autoimmune polyendocrine syndrome.
- Central tolerance in the bone marrow leads to receptor editing or B-cell apoptosis.
- Peripheral Tolerance:
- Peripheral tolerance leads to anergy or apoptosis of T and B cells.
- Fas apoptosis pathway mutations result in autoimmune lymphoproliferative syndrome (ALPS).
- Regulatory T cells suppress autoimmunity by blocking T-cell activation and producing anti-inflammatory cytokines.
- CD25 polymorphisms are associated with autoimmunity (MS and type 1DM)
- FOXP3 mutations lead to IPEX syndrome.
Fundamentals of Pathology
- Macrophages process and present antigens to CD4+ helper T cells via MHC class II
- Helper T cells release IL-12, which induces differentiation into TH1 subtype
- TH1 cells secrete IFN-γ, which converts macrophages to epithelioid histiocytes and giant cells
- Giant cells can be found in granulomas, a hallmark of many inflammatory and infectious diseases
Primary Immunodeficiency
-
DiGeorge Syndrome:
- Developmental failure of the third and fourth pharyngeal pouches
- Caused by 22q11 microdeletion
- Characterized by T-cell deficiency, hypocalcemia, and abnormalities of heart, great vessels, and face.
-
Severe Combined Immunodeficiency (SCID):
- Defective cell-mediated and humoral immunity
- Caused by:
- Cytokine receptor defects: Cytokine signaling is essential for B and T cell proliferation and maturation
- Adenosine deaminase (ADA) deficiency: Buildup of adenosine and deoxyadenosine is toxic to lymphocytes
- MHC class II deficiency: Essential for CD4+ helper T cell activation and cytokine production
- Characterized by susceptibility to fungal, viral, bacterial, and protozoal infections, including opportunistic infections and live vaccines
- Treated with sterile isolation and stem cell transplantation
-
X-Linked Agammaglobulinemia:
- Complete lack of immunoglobulin due to disordered B-cell maturation
- Caused by mutated Bruton tyrosine kinase; X-linked
- Presents after 6 months of age with recurrent bacterial, enterovirus, and Giardia lamblia infections
- Maternal antibodies provide protection during the first 6 months of life, but live vaccines must be avoided
-
Common Variable Immunodeficiency (CVID):
- Low immunoglobulin levels due to B-cell or helper T-cell defects
- Increased risk for bacterial, enterovirus, and Giardia lamblia infections, typically in late childhood
- Increased risk of autoimmune disease and lymphoma
-
IgA Deficiency:
- Most common immunoglobulin deficiency, characterized by low serum and mucosal IgA
- Increased risk for mucosal infections, primarily viral, but most patients are asymptomatic.
-
Hyper-IgM Syndrome:
- High IgM levels due to mutations in CD40L (on helper T cells) or CD40 receptor (on B cells)
- The second signal necessary for B-cell activation cannot be delivered to helper T cells.
- Low IgA, IgG, and IgE result in recurrent pyogenic infections, especially at mucosal sites
-
Wiskott-Aldrich Syndrome:
- Characterized by thrombocytopenia, eczema, and recurrent infections (defective humoral and cellular immunity)
- Caused by mutations in the WASP gene; X-linked
- Bleeding is a major cause of death
-
Complement Deficiencies:
- C5-C9 deficiencies: Increased risk for Neisseria infection (N. gonorrhoeae and N. meningitidis)
- C1 inhibitor deficiency: Hereditary angioedema: Edema of the skin (especially periorbital) and mucosal surfaces
Autoimmune Disorders
- Characterized by immune-mediated damage to self tissues, affecting 1%-2% of the US population.
- Loss of self-tolerance:
- Self-reactive lymphocytes are regularly generated but develop central (thymus and bone marrow) or peripheral tolerance
- Central tolerance in thymus: T-cell apoptosis or generation of regulatory T cells
- AIRE mutations cause autoimmune polyendocrine syndrome.
- Central tolerance in bone marrow: Receptor editing or B-cell apoptosis.
- Peripheral tolerance: Anergy or apoptosis of T and B cells.
- Fas apoptosis pathway mutations lead to autoimmune lymphoproliferative syndrome (ALPS).
- Regulatory T cells suppress autoimmunity:
- Blocking T-cell activation and producing anti-inflammatory cytokines (IL-10 and TGF-β)
- CD25 polymorphisms are associated with autoimmune diseases (MS and type 1DM)
- FOXP3 mutations cause IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked).
- More common in women, particularly those of childbearing age.
- Etiology: Environmental triggers in genetically-susceptible individuals.
- Increased incidence among twins
Fundamentals of Pathology
- Macrophages process and present antigen via MHC class II to CD4+ helper T cells.
- Interaction leads macrophages to secrete IL-12, inducing CD4+ helper T cells to differentiate into TH1 subtype.
- TH1 cells secrete IFN-γ, which converts macrophages to epithelioid histiocytes and giant cells.
Primary Immunodeficiency
-
DiGeorge Syndrome
- Developmental failure of the third and fourth pharyngeal pouches
- Due to 22q11 microdeletion
- Presents with T-cell deficiency (lack of thymus); hypocalcemia (lack of parathyroids); and abnormalities of heart, great vessels, and face.
- Developmental failure of the third and fourth pharyngeal pouches
-
Severe Combined Immunodeficiency (SCID)
- Defective cell-mediated and humoral immunity
- Etiologies include
- Cytokine receptor defects - Cytokine signaling is necessary for proliferation and maturation of B and T cells.
- Adenosine deaminase (ADA) deficiency - ADA is necessary to deaminate adenosine and deoxyadenosine for excretion as waste products; buildup of adenosine and deoxyadenosine is toxic to lymphocytes.
- MHC class II deficiency - MHC class II is necessary for CD4+ helper T cell activation and cytokine production.
- Characterized by susceptibility to fungal, viral, bacterial, and protozoal infections, including opportunistic infections and live vaccines
- Treatment is sterile isolation ('bubble baby') and stem cell transplantation.
-
X-Linked Agammaglobulinemia
- Complete lack of immunoglobulin due to disordered B-cell maturation
- Pre- and pro-B cells cannot mature.
- Due to mutated Bruton tyrosine kinase; X-linked
- Presents after 6 months of life with recurrent bacterial, enterovirus (e.g., polio and coxsackievirus), and Giardia lamblia infections; maternal antibodies present during the first 6 months of life are protective.
- Live vaccines (e.g., polio) must be avoided.
- Complete lack of immunoglobulin due to disordered B-cell maturation
-
Common Variable Immunodeficiency (CVID)
- Low immunoglobulin due to B-cell or helper T-cell defects
- Increased risk for bacterial, enterovirus, and Giardia lamblia infections, usually in late childhood
- Increased risk for autoimmune disease and lymphoma
-
IgA Deficiency
- Low serum and mucosal IgA; most common immunoglobulin deficiency
- Increased risk for mucosal infection, especially viral; however, most patients are asymptomatic.
-
Hyper-IgM Syndrome
- Characterized by elevated IgM
- Due to mutated CD40L (on helper T cells) or CD40 receptor (on B cells)
- Second signal cannot be delivered to helper T cells during B-cell activation.
- Consequently, cytokines necessary for immunoglobulin class switching are not produced.
- Low IgA, IgG, and IgE result in recurrent pyogenic infections (due to poor opsonization), especially at mucosal sites.
-
Wiskott-Aldrich Syndrome
- Characterized by thrombocytopenia, eczema, and recurrent infections (defective humoral and cellular immunity); bleeding is a major cause of death
- Due to mutation in the WASP gene; X-linked
-
Complement Deficiencies
- C5-C9 deficiencies - increased risk for Neisseria infection (N gonorrhoeae and N meningitidis)
- Cl inhibitor deficiency - results in hereditary angioedema, which is characterized by edema of the skin (especially periorbital) and mucosal surfaces
Autoimmune Disorders
- Characterized by immune-mediated damage of self tissues
- US prevalence is 1%-2%.
- Involves loss of self-tolerance
- Self-reactive lymphocytes are regularly generated but develop central (thymus and bone marrow) or peripheral tolerance.
- Central tolerance in thymus leads to T-cell (thymocyte) apoptosis or generation of regulatory T cells.
- AIRE mutations result in autoimmune polyendocrine syndrome.
- Central tolerance in bone marrow leads to receptor editing or B-cell apoptosis.
- Peripheral tolerance leads to anergy or apoptosis of T and B cells.
- Fas apoptosis pathway mutations result in autoimmune lymphoproliferative syndrome (ALPS).
- Regulatory T cells suppress autoimmunity by blocking T-cell activation and producing anti-inflammatory cytokines (IL-10 and TGF-β).
- CD25 polymorphisms are associated with autoimmunity (MS and type 1DM).
- FOXP3 mutations lead to IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked).
- More common in women; classically affects women of childbearing age
- Estrogen may reduce apoptosis of self-reactive B cells.
- Etiology is likely an environmental trigger in genetically-susceptible individuals.
- Increased incidence in twins
Inflammation, Inflammatory Disorders, and Wound Healing
- Granuloma
- Noncaseating
- Caseating
- Angioedema
- Edema of the skin (especially periorbital) and mucosal surfaces
Fundamentals of Pathology
- Macrophages process and present antigens through MHC class II to CD4+ helper T cells
- Macrophages secrete IL-12, inducing CD4+ helper T cells to become T H1 subtype
- TH1 cells secrete IFN- γ, which causes macrophages to turn into epithelioid histiocytes and giant cells
Primary Immunodeficiency
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DiGeorge Syndrome
- Developmental failure of the 3rd and 4th pharyngeal pouches
- Caused by a 22q11 microdeletion
- Presents with T-cell deficiency, hypocalcemia, heart, great vessel, and facial abnormalities
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Severe Combined Immunodeficiency (SCID)
- Defective cell-mediated and humoral immunity
- Cytokine receptor defects lead to impaired B and T cell proliferation and maturation
- Adenosine deaminase (ADA) deficiency leads to toxic buildup of adenosine and deoxyadenosine, harming lymphocytes
- MHC class II deficiency impairs CD4+ helper T cell activation and cytokine production
- Patients are susceptible to fungal, viral, bacterial, and protozoal infections, including opportunistic infections and live vaccines
- Treatment involves sterile isolation and stem cell transplantation
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X-linked Agammaglobulinemia
- Complete lack of immunoglobulin due to disordered B-cell maturation
- Caused by a mutated Bruton tyrosine kinase; X-linked
- Presents after 6 months of age with recurrent bacterial, enterovirus, and Giardia lamblia infections
- Maternal antibodies provide protection during the first 6 months of life
- Live vaccines must be avoided
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Common Variable Immunodeficiency (CVID)
- Low immunoglobulin due to B-cell or helper T-cell defects
- Increased risk for bacterial, enterovirus, and Giardia lamblia infections, usually in late childhood
- Increased risk for autoimmune disease and lymphoma
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IgA Deficiency
- Low serum and mucosal IgA; most common immunoglobulin deficiency
- Increased risk for mucosal infection, especially viral; however, most patients are asymptomatic
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Hyper-IgM Syndrome
- Elevated IgM levels
- Caused by a mutated CD40 ligand (on helper T cells) or CD40 receptor (on B cells)
- Impairs the second signal during B-cell activation, preventing cytokine production for immunoglobulin class switching
- Low IgA, IgG, and IgE lead to recurrent pyogenic infections, especially at mucosal sites
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Wiskott-Aldrich Syndrome
- Thrombocytopenia, eczema, and recurrent infections due to defective humoral and cellular immunity; bleeding is a major hazard
- Caused by a mutation in the WASP gene; X-linked
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Complement Deficiencies
- C5-C9 deficiencies: Increased risk for Neisseria infections (N gonorrhoeae and N meningitidis)
- C1 inhibitor deficiency: Results in hereditary angioedema, characterized by edema of the skin (especially periorbital) and mucosal surfaces
Autoimmune Disorders
- Characterized by immune-mediated damage of self tissues
- US prevalence is 1%-2%
- Involves the loss of self-tolerance
- Self-reactive lymphocytes undergo central (thymus and bone marrow) or peripheral tolerance mechanisms
- Central tolerance:
- In the thymus: Leads to T cell (thymocyte) apoptosis or development of regulatory T cells
- AIRE mutations result in autoimmune polyendocrine syndrome
- In the bone marrow: Leads to receptor editing or B cell apoptosis
- In the thymus: Leads to T cell (thymocyte) apoptosis or development of regulatory T cells
- Peripheral tolerance: Leads to anergy or apoptosis of T and B cells
- Fas apoptosis pathway mutations result in autoimmune lymphoproliferative syndrome (ALPS)
- Regulatory T cells: Suppress autoimmunity by blocking T cell activation and producing anti-inflammatory cytokines (IL-10 and TGF-β)
- CD25 polymorphisms are associated with autoimmunity (MS and type 1 diabetes mellitus)
- FOXP3 mutations lead to IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked)
- More common in women; classically affects those of childbearing age
- Estrogen may reduce apoptosis of self-reactive B cells
- Etiology likely involves environmental triggers in genetically susceptible individuals
- Increased incidence in twins
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