10.1 Immunodeficiency

Podcast

Play an AI-generated podcast conversation about this lesson

Questions and Answers

What is defined as a failure in humoral or cell-mediated limbs of the immune response?

Autoimmunity

Immunodeficiency (correct)

Inflammation

Hypersensitivity

Which type of immunodeficiency is caused by genetic defects in components of the immune system?

Acquired immunodeficiency

Environmental immunodeficiency

Secondary immunodeficiency

Congenital immunodeficiency (correct)

At which stage may genetic defects lead to primary immunodeficiency?

Failure of T cell activation

Failure of antibody production by plasma cells

Failure of antigen presentation

Failure of B cell differentiation into plasma cells (correct)

What distinguishes primary immunodeficiency from secondary immunodeficiency?

Primary is from defects in lymphocytes, secondary is from loss of function Signup and view all the answers

When should primary immunodeficiency be suspected?

In cases of frequent infections Signup and view all the answers

What type of mutation causes the defect related to lysosomal membrane trafficking?

Missense mutation Signup and view all the answers

What is one of the clinical presentations of the condition associated with the lysosomal defect?

Loss of skin color and dilution of hair pigmentation Signup and view all the answers

What is a consequence of reduced neutrophil activity in those with the lysosomal defect?

Increased susceptibility to infections Signup and view all the answers

Which type of eye abnormality is particularly associated with this condition?

Development of cataracts and photophobia Signup and view all the answers

What issues may arise due to the premature release of granule contents by cytotoxic cells?

Increased risk of tissue damage Signup and view all the answers

What is a common characteristic of chronic infections in young animals?

Failure to respond to antibiotic or standard chemotherapy Signup and view all the answers

Which procedure is NOT typically part of the diagnostic work-up for primary immunodeficiency?

Assessment of physical fitness Signup and view all the answers

Which of the following is a goal when diagnosing primary immunodeficiency?

To localize the immunological defect Signup and view all the answers

What is the significance of the CD4+:CD8+ ratio in immunophenotyping?

Usually, more CD4s are present than CD8s Signup and view all the answers

What type of microorganisms may be involved in chronic infections in young animals?

Atypical microorganisms such as saprophytes Signup and view all the answers

Chédiak-Higashi Syndrome is associated with mutations in which gene?

lysosomal transport (CHS1) Signup and view all the answers

Which finding is indicative of a defect in innate immunity?

Deficiencies in complement system function Signup and view all the answers

Which diagnostic approach is used to evaluate cell-mediated immunity?

Assessment of delayed type hypersensitivity using mitogens Signup and view all the answers

What clinical feature is commonly associated with Canine Leukocyte Adhesion Deficiency (CLAD)?

Abnormal blood clotting Signup and view all the answers

What is the primary cause of the defect in Bovine Leukocyte Adhesion Deficiency (BLAD)?

Mutation in CD18 gene Signup and view all the answers

Which of the following best describes the mutation causing Canine Cyclic Neutropenia?

Mutation in AP3β1 gene Signup and view all the answers

What is a significant finding in stained blood smears of animals with severe infections due to CLAD?

Enlarged granules in neutrophils Signup and view all the answers

What is a common outcome for Holstein calves suffering from Bovine Leukocyte Adhesion Deficiency (BLAD)?

Death typically occurs between 2 and 7 months Signup and view all the answers

Which breed is primarily associated with the genetic defect causing Canine Leukocyte Adhesion Deficiency?

Irish Red or White Setters Signup and view all the answers

What immune system component is primarily dysfunctional in cases of CLAD?

Neutrophils Signup and view all the answers

What consequence does the mutation in the CD18 molecule have on neutrophils in CLAD?

Impaired response to chemotactic factors Signup and view all the answers

What is a common consequence of neutropenia observed in dogs with cyclic neutropenia?

Recurrent bacterial and fungal infections Signup and view all the answers

Which process is primarily affected in horses with Severe Combined Immunodeficiency (SCID)?

DNA recombination Signup and view all the answers

What is the primary reason foals with SCID have a healthy appearance at birth?

High levels of maternal antibodies Signup and view all the answers

What defines the lymphocyte status in horses diagnosed with SCID?

Few circulating lymphocytes below 1000/ul Signup and view all the answers

Which statement is true regarding the genetic transmission of Severe Combined Immunodeficiency Disease (SCID) in horses?

It follows an autosomal recessive inheritance pattern Signup and view all the answers

What is a common complication associated with SCID in dogs?

Aplazia of the thymus and lymphoid tissue Signup and view all the answers

What histological feature is characteristic of SCID in horses?

Hypoplasia of primary and secondary lymphatic organs Signup and view all the answers

Which type of infection is commonly seen in foals with SCID?

Bacterial infections Signup and view all the answers

What are the expected immunological findings in dogs with X-linked SCID?

Reduced lymph nodes Signup and view all the answers

What is the molecular defect observed in X-SCID in basset hounds?

Mutation causing premature STOP codon in γ chain Signup and view all the answers

What characterizes primary immunodeficiency disorders?

Result from genetic defects in the immune system Signup and view all the answers

Which of the following stages could lead to a primary immunodeficiency if a genetic defect occurs?

Failure to produce functional neutrophils Signup and view all the answers

Which type of immunodeficiency results from the loss of function of antibodies or lymphocytes?

Acquired immunodeficiency Signup and view all the answers

When considering congenital immunodeficiencies, which condition is most likely due to intrinsic defects in immune cells?

Genetic defects in the immune system Signup and view all the answers

Which option correctly describes a potential diagnosis approach for immunodeficiency?

Blood tests to evaluate immune cell function Signup and view all the answers

What is the effect of the mutation causing the lysosomal trafficking defect?

Increased formation of large secretory lysosomes Signup and view all the answers

Which clinical feature is most likely related to the reduced activity of neutrophils?

Development of cataracts in the eye Signup and view all the answers

What complication may result from the premature release of granule contents by cytotoxic cells?

Development of hematomas at injection sites Signup and view all the answers

Which of the following is a consequence of lysosomal accumulation in leukocytes?

Development of large granules in affected cells Signup and view all the answers

What is an expected outcome of the lysosomal defect on the immune system?

Heightened susceptibility to upper respiratory infections Signup and view all the answers

What is a common laboratory test included in the diagnostic procedures for primary immunodeficiency?

Screening for infectious diseases Signup and view all the answers

Which of the following findings may indicate a defect in adaptive immunity?

Failure to respond to vaccine antigens Signup and view all the answers

What does the CD4+:CD8+ ratio typically indicate in immunophenotyping?

More CD4 T cells than CD8 T cells Signup and view all the answers

Which of the following conditions is classified as an immunodeficiency associated with innate immunity?

Chédiak-Higashi Syndrome Signup and view all the answers

In which type of animals has the Chédiak-Higashi Syndrome been observed?

In a wide range of species including humans and cattle Signup and view all the answers

What is the primary aim when diagnosing primary immunodeficiency?

To localize the immunological defect Signup and view all the answers

What unique feature is often observed in tests of animals with Chédiak-Higashi Syndrome?

Giant lysosomal granules in leukocytes Signup and view all the answers

What should be done to confirm atypical results in immunological testing?

Confirm results at least twice Signup and view all the answers

What is a primary clinical feature of Canine Leukocyte Adhesion Deficiency (CLAD)?

Delayed wound healing Signup and view all the answers

Which mutation is associated with Bovine Leukocyte Adhesion Deficiency (BLAD)?

Replacement of Asp with Gly Signup and view all the answers

What is a significant characteristic of neutrophils in animals affected by CLAD?

They fail to extravasate to sites of inflammation. Signup and view all the answers

Which breed is primarily associated with Canine Leukocyte Adhesion Deficiency?

Irish Red Setter Signup and view all the answers

Which clinical outcome is observed in Holstein calves suffering from BLAD?

Severe infections and stunted growth Signup and view all the answers

What defect underlies the neutrophil function in Canine Cyclic Neutropenia?

Mutation in AP3β1 gene Signup and view all the answers

What is the result of the mutation in the β chain of CD18 in cases of CLAD?

Incorrect protein production disrupting disulfide bonds Signup and view all the answers

What laboratory finding is often associated with dogs suffering from CLAD?

Neutrophilia and leukocytosis Signup and view all the answers

What typical change occurs in neutrophil numbers in the context of cyclic neutropenia?

Neutrophil counts drop every 11-12 days for at least 3 days. Signup and view all the answers

Which of the following is NOT a pathology associated with cyclic neutropenia?

Hypertension Signup and view all the answers

What is primarily impaired in horses with Severe Combined Immunodeficiency (SCID)?

Lymphocyte production Signup and view all the answers

What is one of the clinical features of SCID in horses after two months of age?

Development of agammaglobulinemia Signup and view all the answers

What is the genetic inheritance pattern of Severe Combined Immunodeficiency in dogs?

Autosomal recessive Signup and view all the answers

What leads to the dysfunction of lymphocytes in X-linked SCID in canines?

Mutation in the γ chain of the IL-2 receptor Signup and view all the answers

Which of the following lab findings confirms SCID in horses?

Few circulating lymphocytes below 1000/ul Signup and view all the answers

What is a common outcome for foals diagnosed with SCID?

Death from severe infections Signup and view all the answers

What is a histological finding typical of SCID in horses?

Hypoplasia of primary and secondary lymphatic organs Signup and view all the answers

What mutation causes the dysfunction of lymphocytes in Corgis with X-SCID?

Insertion of cytosine that creates a premature STOP codon Signup and view all the answers

What best describes secondary immunodeficiency?

It results from a loss of function of antibodies and/or lymphocytes. Signup and view all the answers

Which stage of immune cell development could lead to primary immunodeficiency if a genetic defect occurs?

Failure of B cell development. Signup and view all the answers

What is a potential cause of congenital immunodeficiency?

Genetic mutations affecting immune system components. Signup and view all the answers

Which of the following describes a feature of primary immunodeficiencies?

They involve a failure in one or more immune system components. Signup and view all the answers

What type of leukocyte activity might be impaired in congenital immunodeficiency?

Neutrophil chemotaxis and phagocytosis. Signup and view all the answers

What is the primary consequence of the mutation affecting lysosomal membrane trafficking?

Development of large secretory lysosomes in various cells Signup and view all the answers

Which symptom is commonly associated with the lysosomal defect in leukocytes?

Reduced pigmentation in skin and hair Signup and view all the answers

What complication may arise from the abnormal granule release in cytotoxic cells?

Inflammatory response leading to skin lesions Signup and view all the answers

How does the defect in neutrophils contribute to patient susceptibility to infections?

They exhibit reduced intracellular cytotoxicity Signup and view all the answers

Which abnormal eye condition is associated with lysosomal dysfunction?

Cataracts Signup and view all the answers

What is a common laboratory test used to assess immune system function in suspected primary immunodeficiency cases?

Complete blood count with differential Signup and view all the answers

Which of the following immunological defects is characterized by insufficient functioning of the NK cells?

Immunodeficiencies associated with innate immunity Signup and view all the answers

What diagnostic procedure is specifically utilized to evaluate allergic reactions or autoimmune conditions during immunological assessments?

Assessment of delayed type hypersensitivity using mitogens Signup and view all the answers

Which condition may involve multiple site infections in young animals, indicating a potential underlying immunodeficiency?

Primary immunodeficiency Signup and view all the answers

What clinical finding may be indicative of primary immunodeficiency in animals with a chronic infection?

Persistent leukopenia Signup and view all the answers

Which breed is NOT commonly associated with Chédiak-Higashi Syndrome?

Beagle Signup and view all the answers

In primary immunodeficiency diagnostics, what does an abnormal CD4+:CD8+ ratio typically indicate?

Defect in cellular immunity Signup and view all the answers

Which diagnostic technique assesses the function of lymphocytes in peripheral blood?

Immunophenotyping Signup and view all the answers

What is the primary clinical outcome of Canine Leukocyte Adhesion Deficiency (CLAD)?

Inability to heal wounds properly Signup and view all the answers

What specific mutation is responsible for the defect in Canine Cyclic Neutropenia?

Missense mutation in the AP3β1 gene Signup and view all the answers

Which breed is most commonly associated with Bovine Leukocyte Adhesion Deficiency (BLAD)?

Holstein calves Signup and view all the answers

How does the CD18 mutation affect the neutrophils in CLAD?

Reduced migration to infection sites Signup and view all the answers

What is a common laboratory finding in blood smears of animals with CLAD?

Enlarged granules in neutrophils Signup and view all the answers

What is a clinical feature observed in both Canine and Bovine Leukocyte Adhesion Deficiency?

Delayed wound healing Signup and view all the answers

What is the common characteristic of leukocyte counts in CLAD-affected animals?

Leukocytosis with neutrophilia Signup and view all the answers

What is the primary reason for the death of Holstein calves affected by BLAD?

Severe infections due to leukocyte dysfunction Signup and view all the answers

What is a characteristic feature of cyclic neutropenia in affected animals?

Neutrophil count may increase every 7 days Signup and view all the answers

Which of the following conditions is primarily associated with SCID in horses?

Few circulating lymphocytes below 1000/µL Signup and view all the answers

What mutation is responsible for X-linked SCID in certain dog breeds?

Frameshift mutation in the gamma chain of IL-2 receptor Signup and view all the answers

What is a common clinical manifestation of Severe Combined Immunodeficiency (SCID) in horses?

Frequent viral infections after 2 months of age Signup and view all the answers

What is the predicted percentage of foals that would be affected from two heterozygous parents for the SCID gene?

25% Signup and view all the answers

Which statement regarding neutrophil behavior in cyclic neutropenia is accurate?

Neutrophil loss occurs every 11-12 days Signup and view all the answers

Which laboratory finding is indicative of SCID in horses?

Histological hypoplasia of lymphatic organs Signup and view all the answers

What complication often leads to death in foals with SCID?

Severe bacterial, viral, and fungal infections Signup and view all the answers

Which immunological defect is characteristic of SCID in dogs?

Agammaglobulinemia and lymphopenia Signup and view all the answers

Study Notes

Immunodeficiency Overview

Immunodeficiency is a failure in humoral or cell-mediated immune responses.
Primary immunodeficiency is due to intrinsic defects in T and/or B lymphocytes, also called congenital immunodeficiency.
Secondary immunodeficiency arises from loss of function in antibodies and/or lymphocytes, also called acquired immunodeficiency.
Immunodeficiency can involve defective leukocytes or the complement system.

Primary Immunodeficiency

Results from genetic defects in one or more components of the immune system.
Defects occur at various stages of immune cell development, including:
- Pluripotent stem cell differentiation
- Lymphoid/myeloid lineage differentiation from stem cells
- T cell development
- B cell development
- B cell differentiation into plasma cells
- Plasma cell production of specific immunoglobulin classes
- Functional neutrophil and macrophage production
- Complement component production

Suspecting Primary Immunodeficiencies

Signs of primary immunodeficiency include:
- Chronic or recurrent infections in young animals
- Failure to respond to antibiotics or chemotherapy
- Multiple site infections in young animals or littermates
- Infection with atypical microorganisms (e.g., saprophytes or commensals)
- Lack of response to vaccine antigens
- Persistent leukocytosis or hypergammaglobulinemia
- Persistent leukopenia or hypogammaglobulinemia
- Allergy or concurrent autoimmune disease

Diagnosing Primary Immunodeficiencies

The goal is localizing the immunological defect to one or more components of the immune system.
Ideally, use a full panel of tests targeting cell-mediated and humoral immunity.
Diagnostic procedures could include:
- Hematology profiles
- Bone marrow and lymph node biopsies
- Serum complement component determination
- Screening for infectious diseases using available serological and molecular techniques
- Necropsy of dead littermates
- Determination of antibody response to vaccine antigens
- Immunophenotyping of peripheral blood lymphocytes (particularly CD4+:CD8+ ratio)
- Functional testing for neutrophils and macrophages
- Assessment of delayed-type hypersensitivity (Type IV) using mitogens like phytohemagglutinin (PHA) injected subcutaneously
- Confirm atypical results multiple times

Genetic Testing

Genetic testing for some animal diseases, like X-linked Severe Combined Immune-deficiency (SCID), is becoming more available.

Immunodeficiencies Associated with Innate Immunity

May involve defects in various stages of phagocytosis.
Deficiencies in complement system function.
Dysfunction of natural killer (NK) cells.

Chédiak-Higashi Syndrome (CHS)

Found in various animals (mink, cats, etc.) and humans.
Caused by a mutation in the lyst (CHS1) gene, which codes for a protein regulating lysosomal membrane trafficking.
The mutation is a missense type replacement.
Defects lead to large secretory lysosomes in neutrophils, monocytes, eosinophils, and melanocytes.
Characteristic large granules are present in these cells.
Clinical presentation includes:
- Loss of skin color and hair pigment dilution.
- Eye abnormalities, such as cataracts and photophobia.
- Increased susceptibility to infections, mainly in the upper respiratory tract.
- Tendency to bleed abnormally after surgery or injection sites; possible acute hemorrhage.
- Dysfunction of NK cells, neutrophils, and cytotoxic T cells.
- Increased susceptibility to tumors in young animals.
Diagnosis is via stained blood smears (revealing enlarged granules in neutrophils) and molecular testing (humans).
Treatment is symptomatic.

Canine Leukocyte Adhesion Deficiency (CLAD)

Lack of integrin CD11b/CD18 (Mac-1).
Neutrophils don't react to chemotactic factors.
Neutrophils cannot bind to endothelial cells.
Clinical features include:
- Death due to severe infections (lymphadenopathy, impaired pus formation, delayed wound healing).
- Leukocytosis (>200,000/µL), neutrophilia, eosinophilia.
- Lack of leukocyte migration to infection sites.
- Recurrent infections, despite high neutrophil counts
- Abnormal blood clotting tendencies.
The defect is typically found in Irish Red or White Setters.
Molecular mechanism: A single missense mutation occurs at position 107 in the β chain of CD18 (integrin β2,) replacing cysteine with serine. This disrupts disulfide bonds, impacting CD18 structure and function; CD11b expression is affected.
Diagnosis involves analysis of blood samples.
Treatment is symptomatic.

Bovine Leukocyte Adhesion Deficiency (BLAD)

Found in Holstein calves.
Similar clinical presentation to CLAD.
Calves die between 2 and 7 months of age.

Common Variable Immunodeficiency (CVID)

B lymphocytes do not efficiently produce enough immunoglobulins.
- Mostly due to lack of suitable stimulation of B cells by helper T cells.
- Defect commonly appears in older horses (over 3 years).
- Leads to recurrent infections, bacterial meningitis.
- Trace levels of IgM and IgG while IgG3 levels may be normal .
- Normal or low T cell numbers
- Few B lymphocytes in lymphoid tissues, marrow, and circulation
- In some cases, acute hepatitis can be present.
  - Defects due to co-stimulatory molecule ICOS (ICOSL required for optimal lymphocyte stimulation).
  - Co-stimulation via ICOS/ICOSL is necessary for optimal lymphocyte stimulation

Severe Combined Immunodeficiency (SCID)

A hereditary disease most common in purebred Arabian horses.
Characterized by insufficient T and B lymphocyte production with very low numbers in circulation.
Foals appear healthy at birth, but health problems start around 2 months of age.
If foals receive sufficient antibodies in colostrum and milk, protection is offered.
Diagnositic criteria include:
- Few circulating lymphocytes (<1000/µL).
- Lack of IgM in serum (before suckling)
Histological examination shows hypoplasia of primary and secondary lymphatic organs (thymus, spleen, lymph nodes).
SCID in horses is caused by a defect in a DNA-dependent enzyme responsible for DNA recombination (DNA-PKcs).
- Mutation: Removal of 5 nucleotides in gene encoding DNA-PKcs, resulting in a loss of 967 amino acids in the protein.
- This prevents proper recombination of variable regions in antibodies and T cell receptors (TCR), preventing lymphocyte function.
SCID in dogs is autosomal recessive in Jack Russell terriers.

X-linked Severe Combined Immunodeficiency (X-SCID)

An inherited disease that only affects males.
Occurs in bassets and corgis.
Affected dogs often lack lymph nodes.
The cause is a mutation in the gene encoding the γ chain of the IL-2 receptor (IL-2R).
Removal of 4 nucleotides leads to a premature stop codon.
Only part of the functional protein is generated.
- Lymphocytes lose responsiveness to IL-2 and other cytokines needing a γ-chain receptor.
Affected animals do not generate mature T lymphocytes.

Selective Immunoglobulin Isotype Deficiencies

Selective involvements of only some Ig isotypes.
Most common is IgA deficiency.
- Results from a block in B cell differentiation into IgA-producing antibody-secreting cells.
  - Occasionally, homozygous deletions of genes for constant regions are the cause.

Secondary Immunodeficiencies

Immune system damage from infectious agents (viruses), toxins, stress, malnutrition, and old age.

Virus-Induced Immunosuppression

Viruses can damage primary or secondary lymphatic organs.
Causes lymphopenia.
Reduces lymphocyte reactivity to stimulation by mitogens or specific antigens.
May reduce immunoglobulin levels (hypogammaglobulinemia).
Various examples of viruses linked to damage are provided.

Canine Distemper Virus

Damages T and B lymphocytes, spleen, MALT, and thymus.
Causes lymphopenia and immunosuppression.
Reduces production of IL-1 and IL-12.
Increases susceptibility to Pneumocystis carinii pneumonia.
Virus binding to activated T cells facilitates replication and cell destruction.

Feline Leukemia Virus

Has tropism for lymphoid tissue, specifically targeting T lymphocytes.
Reduces CD4+ T cell numbers, causing wasting syndrome.
Recurrent infections and atrophy of the thymus.
Secondary infection severity influences lymphoid tissue development (atrophy or hyperplasia).
Leads to immunosuppression.

Feline Immunodeficiency Virus

An infectious disease in cats.
Replicates in lymphocytes (mostly CD4+ T cells, B cells, and macrophages).
Binds to CD134 and CD184 (CXCR4) on activated CD4+ cells, leading to a reduction in CD4+ cell count.
Causes a reduction in IL-2 production, and increase in IL-10 production.

Immunosenescence

Age-related decline in immune system function.
The breakdown of various immune cell types is illustrated in the diagram.

Studying That Suits You

Use AI to generate personalized quizzes and flashcards to suit your learning preferences.

Description

Test your knowledge on the various types of immunodeficiencies, their causes, and clinical presentations. This quiz addresses both primary and secondary immunodeficiencies and the genetic mutations involved. Challenge yourself with specific questions about immune response failures and lysosomal defects.