Immunodeficiency
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Immunodeficiency. Primary (congenital) immunodeficiencies: inherited disorders that arise from a genetic defect Secondary immunodeficiencies: arise from extrinsic causes Malnutrition Irradiation Infections Immunosuppressive therapy. How Immunodeficiency Diseases Present.

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Immunodeficiency
Immunodeficiency

  • Primary (congenital) immunodeficiencies: inherited disorders that arise from a genetic defect

  • Secondary immunodeficiencies: arise from extrinsic causes

    • Malnutrition

    • Irradiation

    • Infections

    • Immunosuppressive therapy


How immunodeficiency diseases present
How Immunodeficiency Diseases Present

  • Recurrent or chronic pyogenic (pus-forming) infections

    • These indicate defects in

      • Antibodies and/or B cells

      • Complement components

      • Phagocytes

    • Common agents are encapsulated bacteria

      • Streptococcus pneumoniae

      • Neisseria meningitidis

      • Staphylococcus aureus

      • Haemophilus influenzae

    • Common clinical manifestations

      • Bacterial pneumonia

      • Otitis media

      • Sinusitis

      • Meningitis

      • Osteomyelitis

      • Infections with gram-negative enterics


How immunodeficiency diseases present1
How Immunodeficiency Diseases Present

  • Recurrent or chronic opportunistic infections

    • These indicate defects in T cells

    • Common agents

      • Viruses, e.g. rotavirus, HIV

      • Fungi, e.g. Candida, Pneumocystis jiroveci

      • Protozoans, e.g. Toxoplasma

      • Atypical mycobacteria

    • Leads to combined deficiency of CMI and humoral immunity

  • Cancer

    • Usually indicates T cell deficiency

    • EBV, Kaposi sarcoma


How immunodeficiency diseases present2
How Immunodeficiency Diseases Present

  • Diseases that present as antibody deficiencies

    • X-linked agammaglobulinemia

    • Selective IgA and IgG subclass deficiencies

    • Hyper IgM syndrome

    • Common variable immunodeficiency

    • Transient hypogammaglobulinemia of infancy

  • Diseases that present as T cell or combined deficiencies

    • SCID

    • DiGeorge syndrome

    • Hereditary ataxia-telangiectasia

    • Wiskott-Aldrich syndrome

  • Phagocytic cell deficiencies

    • Chronic granulomatous disease

    • Leukocyte adhesion deficiency

    • Chédiak-Higashi disease

    • Hyper IgE (Job) syndrome

  • Complement deficiencies

    • Hereditary angioedema

    • Paroxysmal nocturnal hemoglobinuria

    • Component deficiencies


X linked infantile bruton s agammaglobulinemia xla
X-linked Infantile (Bruton’s) Agammaglobulinemia (XLA)

  • Males only; rare

  • btk gene defect

  • First presents at 5-6 months of age

  • Repeated pyogenic infections that don’t respond to antibiotics, Giardia lamblia

  • Passive immunity from mom has dissipated

  • Near absence of all antibodies: no response to vaccines, no isohemagglutinins

  • Scant lymphoid tissue

  • By 20-30 y, bronchiectasis may cause death

  • T cells OK, so live vaccines OK

Antibody deficiencies


Selective iga deficiency
Selective IgA Deficiency

  • Common in Caucasians

  • Serum IgA <50 mg/ml

  • Sinopulmonary infections, celiac disease, immune complex disease

  • May be asymptomatic

  • May progress to CVID

  • Persons with IgA deficiency may possess IgE directed toward IgA

    • Wash those RBCs before transfusion!

Antibody deficiencies


Selective igg subclass deficiency
Selective IgG Subclass Deficiency

  • Total serum IgG may be normal

  • IgG3 deficiency most common in adults

  • IgG2 deficiency most common in children

  • May lead to increased bacterial infections, or have no problems

Antibody deficiencies


Hyper igm syndrome
Hyper-IgM Syndrome

  • Low levels of IgG and IgA with increased levels of IgM

  • IgM autoantibodies to neutrophils, platelets, tissue antigens

  • B cells can’t class-switch

  • X-linked (70%)

    • T cell defect in CD40L

    • No T cell activation of macrophages

    • Defective CMI  P. jiroveci

  • Autosomal recessive (30%)

    • Defect in CD40 gene in B cells and APCs

    • Defect in activation-induced cytidine deaminase (AID) gene in the B cell

Antibody deficiencies


Common variable immunodeficiency cvid
Common Variable Immunodeficiency (CVID)

  • Common variable hypogammaglobulinemia

  • Males and females

  • Usual onset 15-35 y

  • May follow EBV infection

  • Associated with selective IgA deficiency

  • Low serum IgG and IgA, low or normal IgM, low or normal B cell count

  • Mothers cannot confer passive protection on infants

  • Marked by

    • Pyogenic bacterial infections

    • Autoimmune diseases, especially pernicious anemia

    • Giardiasis

    • Malignant neoplasms

  • Variable defects

Antibody deficiencies


Transient hypogammaglobulinemia of infancy
Transient Hypogammaglobulinemia of Infancy

  • Males and females

  • Presents at 5-6 months

  • May persist through 2-3 years of age

  • IgG absent, IgM and IgA normal

  • B cells are normal

  • No class switching to IgG due to TH defect

  • TH defect precludes live viral vaccines!

  • Normal numbers of B cells in blood, unlike XLA

Antibody deficiencies


Treatments for antibody deficiencies
Treatments for Antibody Deficiencies

  • Broad-spectrum antibiotics

  • Intravenous immune globulin – contains mostly IgG

  • Do not treat selective IgA deficiency with IVIG

    • Patients may possess IgE specific for IgA

    • Administration of IgA may cause anaphylaxis

    • If your patient is both IgG and IgA deficient, correct the IgG deficiency with an IVIG prep that contains no IgA – Gammagard S/D

    • Treat IgA deficiency with antibiotics

Antibody deficiencies


Severe combined immunodeficiency scid
Severe Combined Immunodeficiency (SCID)

  • Heterogeneous disorder with defects in CMI and antibody

  • Patients susceptible to all types of infections – rotavirus, CMV, candidiasis, Pneumocystis jiroveci

  • Diarrhea and pneumonia

  • Vaccination with live microbes is lethal

  • Symptoms occur earlier than in XLA

  • Fatal before age 1 year if untreated

  • Treat with bone marrow transplant

  • There are three phenotypes: T–B+, T–B–, T+B+

T/combined


Severe combined immunodeficiency scid1
Severe Combined Immunodeficiency (SCID)

  • T–B+ subgroup

    • X-linked

      • Defect in the g chain of the receptor for IL-2, 4, 7, 9, and 15

      • Recessive mutation – heterozygous females are phenotypically normal carriers

Failure to activate transcription of specific genes

T/combined


Severe combined immunodeficiency scid2
Severe Combined Immunodeficiency (SCID)

  • T–B+ subgroup

    • Autosomal recessive

      • Defect in the  chain of IL-7 or in the JAK3 tyrosine kinase

      • JAK3 tyrosine kinase is responsible for transmitting signals from the  chain of the receptors for IL-2, 4, 7, 9, 15

T/combined


Scid continued
SCID continued

  • T-B- subgroup

    • Defects in adenosine deaminase (ADA)

      • Accumulation of intracellular S-adenosylhomocysteine and dATP

      • T and B lymphocytes are particularly susceptible

        • Lack compensatory 5’-nucleotidase

      • Treat with gene therapy, continuous enzyme supplementation, or bone marrow transplant

    • RAG-1 and RAG-2 deficiencies

      • Stops B and T maturation at pre-B and pre-T stages

T/combined


Scid continued1
SCID continued

  • T+B+ subgroup

    • Bare lymphocyte syndrome

      • Cells lack MHC class II

      • No collaboration between APCs and TH cells

    • Class I MHC/TAP deficiency

      • Defect in TAP transporter gene

      • No loading of processed peptide into MHC class I groove

      • Empty MHC class I molecule is unstable and not expressed on APC surface

T/combined


Congenital thymic aplasia digeorge syndrome
Congenital Thymic Aplasia (DiGeorge Syndrome)

  • Thymus (and parathyroid) fails to develop from 3rd & 4th pharyngeal pouches

  • Few or no T cells

  • Hypocalcemic tetany 24 h due to hypoparathyroidism

  • Congenital defects in heart and kidneys

  • Hypertelorism, low-set ears, shortened philtrum

T/combined


Digeorge syndrome continued
DiGeorge Syndrome continued

  • B cells present, but no IgG production

  • No live vaccines!

  • Not hereditary, deletion in chromosome 22

  • Immunodeficiency treated by bone marrow transplant

    • BMT may not be necessary

    • T cell function may be normal by age 5 years

  • Nude mouse model

T/combined


Hereditary ataxia telangiectasia
Hereditary Ataxia-Telangiectasia

  • Neurologic, immunologic, endocrine, hepatic and cutaneous abnormalities

  • Defective DNA repair gene

  • DNA breaks in chromosomes 7 and 14 encoding TCR and heavy chain go unrepaired

  • Presents at 18 months: wobbly gait (ataxia)

  • Telangiectasia (dilated capillaries) appear on skin and in eyes by 6 y

  • Severe sinus and lung infections

  • Autoimmune disorders and cancer

T/combined


Wiskott aldrich syndrome
Wiskott-Aldrich Syndrome

  • X-linked

  • wasp gene defect coding for cytoskeletal protein

    • Decreased signal transduction through adapter proteins

    • Accelerates Fas-mediated lymphocyte apoptosis

  • Presents at ~20 months

    • Thrombocytopenia leading to bleeding disorder

    • Small platelets

    • Low IgM, normal IgG, high IgA and IgE

    • Eczema

    • Pyogenic and opportunistic infections

    • Cannot respond to polysaccharide vaccines

  • Tx: antibiotics, anti-virals, bone marrow transplant

  • Life expectancy 3 y without antibiotics, 30 y with antibiotics but without immune reconstitution

  • Death due to lymphoid malignancy

T/combined


Chronic granulomatous disease cgd
Chronic Granulomatous Disease (CGD)

  • Phagocytes lack functional NADPH oxidase  no superoxide, no peroxide, leads to intracellular survival of fungi and bacteria

  • Usual onset early childhood

  • 2/3 of cases are X-linked

  • Signs and symptoms

    • Repeated infections by catalase positive bacteria and fungi

      • Staphylococcus, Serratia, Burkholderia, Aspergillus, Candida

    • Granulomas

    • Pneumonia

    • Lymphadenitis

    • Abscesses in skin, liver and viscera

  • Tx

    • Antimicrobials, aggressive immunization

    • IFN

  • NBT test for diagnosis

    • CGD phagocytes fail to reduce NBT to formazan

    • In CGD phagocytes, there’s no color change from yellow to purple

Normal

CGD

Phagocyte defects


Leukocyte adhesion deficiency
Leukocyte Adhesion Deficiency

  • LAD I

    • Defective CD18 (an integrin b chain) common to LFA-1 and CR3

    • No extravasation

    • Leukocytosis

    • No pus formation

    • No phagocytosis of microbes opsonized by complement

    • Severe infections spread rapidly, especially in mouth and GI tract

    • Treat with bone marrow transplant

CD15

  • LAD II

  • – Impaired fucose metabolism, e.g. sialyl Lewis X/CD15

Phagocyte defects


Ch diak higashi disease
Chédiak-Higashi Disease

  • Defective granules in lysosomes and melanosomes

  • No intracellular killing

  • Signs and symptoms

    • Recurrent Staphylococcus, Streptococcus and Pseudomonas infections of skin, lungs, respiratory tract

    • Lymphoma-like infiltration of organs by leukocytes with giant cytoplasmic granules

    • Hypopigmentation because of faulty melanosomes

  • NK cell activity depressed

  • Tx: antibiotics, some BMT

  • Poor prognosis

Phagocyte defects


Job s syndrome hyper ige syndrome
Job’s Syndrome (Hyper IgE Syndrome)

  • Immunologic features

    • Recurrent boils and cold staphylococcal abscesses

    • IgE and chronic eczema

    • Recurrent cystic lung disease with S. aureus and C. albicans

    • Mucocutaneous candidiasis

    • Otitis media

    • Eosinophilia

  • Non-immunologic features (not always present)

    • Bone fractures, other skeletal abnormalities

    • Coarse facial features, e.g. prominent brow

    • Joint hyperextensibility

    • Retained primary dentition

  • Causative effects variable

  • Tx: antibiotics and anti-fungals

  • Tx for eczema: corticosteroids, tacrolimus as last resort

Phagocyte defects


Hereditary angioedema hae
Hereditary Angioedema (HAE)

  • Deficiency in C1 esterase inhibitor allows C1qr2s2 and plasmin to function unregulated

    • Type I (85%) – low levels of normal C1INH

    • Type II (15%) – normal or high levels of dysfunctional C1INH

  • Inherited or spontaneous mutations (acquired AE)

  • Unchecked activation of classical pathway consumes C4 and C2

  • Low levels of C4 are diagnostic

  • Signs and symptoms

    • Edema caused by C2 product from plasmin cleavage

    • Local edema of hands, face, arms, legs, genitals, buttocks

    • Edema of stomach, intestines, bladder causes abdominal pain, constipation or diarrhea, cramps, vomiting

    • Laryngeal edema can lead to suffocation

    • Edema may be preceded by tingling and erythema

    • Edema caused by stress or trauma, e.g. dental procedure

Complement defects


Hereditary angioedema hae1
Hereditary Angioedema (HAE)

  • Prophylaxis before dental or surgical procedures

    • Fresh frozen plasma to replace C1INH

    • Danazol to increase C4

  • Treatment of on-going attack

    • Maintain airway

    • Narcotics for abdominal pain

    • IV fluids for hemodynamic stability

Complement defects


Paroxysmal nocturnal hemoglobinuria pnh
Paroxysmal Nocturnal Hemoglobinuria (PNH)

  • Stem cell defect in GPI anchors of complement regulators that protect human cells

    • Decay-accelerating factor (DAF)

    • Homologous restriction factor (HRF)

    • CD59

  • Dark urine due to RBC lysis

  • Triad of symptoms

    • Anemia due to RBC lysis

    • Pancytopenia due to lysis of RBCs, WBCs, and platelets

    • Thrombosis in large vessels of liver, abdomen, brain, dermis

      • Thrombosis usual cause of death in PNH patients

      • Budd-Chiari syndrome – severe abdominal pain, enlarging liver, ascites

  • Additional signs and symptoms

    • Weakness, dyspnea, pallor, splenomegaly, iron deficiency, bleeding disorders, renal failure, severe headaches and eye pain (thrombotic vascular occlusion), chronic infections

Complement defects


Paroxysmal nocturnal hemoglobinuria pnh1
Paroxysmal Nocturnal Hemoglobinuria (PNH)

  • Median survival 10 years

  • Variable age at onset

  • Dx

    • Flow cytometry to detect DAF and CD59 on peripheral blood cells

    • Sugar water test

      • Reduce salt concentration by adding isotonic sucrose

      • This causes lysis of PNH RBCs

    • Ham test

      • Acidify human serum to pH 6.2

      • Add RBCs from PNH patient

      • RBCs will lyse if GPI-deficient

  • Tx

    • For hemolysis: prednisone or eculizumab (Mab to C5)

    • For anemia: iron supplements, packed RBCs, erythropoietin

    • For thrombosis: heparin for emergencies, then maintain patient on Coumadin anticoagulant

    • Stem cell transplant for aplastic anemia or leukemia

Complement defects


Complement component deficiencies
Complement Component Deficiencies

  • Deficiency in C5-C8

    • Increased incidence of Neisseria infections

    • Vaccination with MCV4 or MPSV4 helps prevent infections

  • Deficiency in C3, Factor H, Factor I

    • Recurrent pyogenic bacterial infections

    • Vaccinate against Neisseria meningitidis and Streptococcus pneumoniae

  • Deficiency in C1, C2, C4

    • Immune complex disease

    • SLE

  • Diagnosis of component deficiencies by CH50 assay

    • Perform dilution series of patient serum

    • Add serum dilutions to constant amount of sheep red blood cells coated with IgG

    • The complement titer is the reciprocal of the highest serum dilution to lyse 50% of the RBCs

Complement defects


Secondary immunodeficiencies
Secondary Immunodeficiencies

  • Result from extrinsic causes

    • Poor nutrition is the leading cause world-wide

    • Cancer therapy, drugs to prevent graft rejection

    • Inflammatory bowel disease, skin burns – loss of antibodies

    • Surgical splenectomy

    • Infections of leukocytes

Secondary immunodeficiencies


Secondary immunodeficiencies1
Secondary Immunodeficiencies

  • Acquired immunodeficiency syndrome (AIDS)

    • Caused by human immunodeficiency virus (HIV)

    • Transmission

      • Sexual contact

      • Transfer of blood products

      • Contaminated needles

      • Mother to child during pregnancy, birth, or breast-feeding

    • HIV infects all cells expressing CD4

      • TH cells

      • Monocytes/macrophages

      • Dendritic cells

      • Langerhans cells

      • Microglial cells

Secondary immunodeficiencies


Secondary immunodeficiencies aids
Secondary Immunodeficiencies - AIDS

  • HIV also requires chemokine receptor as co-receptor

    • M-tropic viruses use CCR5

      • Prefer macrophage host cells

      • M-tropism early in disease

      • Persons with mutant CCR5 are HIV-resistant

    • T-tropic viruses use CXCR4

      • Prefer TH host cells

    • May be evolution from M-tropic to T-tropic as gp120 mutates

    • Early signs and symptoms

      • Fevers caused by IL-1 production

      • Night sweats

      • Diarrhea

      • Cachexia due to TNF release

Secondary immunodeficiencies


Immunodeficiency

Secondary Immunodeficiencies - AIDS

  • Later

    • Profound loss of CD4+ TH cells

    • <200 TH cells/l

    • TH:Tc reverses to 1:2

    • Loss of humoral and cell-mediated immunity

  • Recurrent/opportunistic infections

    • Varicella-zoster – shingles

    • Herpes simplex – genital and anal lesions

    • Candida albicans – oral thrush

    • Cryptosporidium, Campylobacter, Salmonella, microsporidia – diarrhea

    • Pneumocystis, Mycobacterium, fungi – pneumonia

    • Toxoplasma – brain abscesses

    • CMV – esophageal ulceration, chorioretinitis, CNS

    • JC virus – progressive multifocal leukoencephalopathy

  • Lymphoma (EBV), Kaposi sarcoma (HHV-8), dementia, paralysis

Secondary immunodeficiencies


Immunodeficiency

Kaposi’s sarcoma lesions

Pneumocystis jiroveci pneumonia

Cryptosporidium

CT

Cerebral toxoplasmosis

Small bowel

Secondary immunodeficiencies


Immunodeficiency

Secondary Immunodeficiencies - AIDS

  • No vaccine, no cure

  • Tx: highly active antiretroviral therapy (HAART)

    • Combination therapy from these categories

      • Nucleoside reverse transcriptase inhibitors

      • Non-nucleoside reverse transcriptase inhibitors

      • Protease inhibitors

      • Inhibitors of viral entry – chemokine receptor antagonists, inhibitors of viral-cell membrane fusion

      • Integrase inhibitors under development – prevent integration of proviral DNA into host cell genome

Secondary immunodeficiencies