Week 6 Clinical Correlations

DiGeorge Syndrome

AUTOSOMAL DOMINANT or DE NOVO

• A deletion on chromosome 22 (22q11.2) - abnormal

embryologic development

-> resulting in deformities/absence of midline structures

• thymus is absent, there is no T cell immunity

-> Thymus transplant

• can be complete or partial

• CATCH-22: Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcemia - chromosome 22q11.2

-> FISH probe goes fishing for micro deletions

Reticular Dysgenesis

AUTOSOMAL RECESSIVE

• type of SCID - affects both innate/adaptive

-> Agranulocytosis (innate immune system) with lymphopenia (adaptive immune system) and Sensorineural deafness

• can be treated with hematopoietic stem cell transplantation (HSCT)

SARS-CoV-2

• Viral RNA - PAMP -> activates various PRRs (TLRs, RLRs, NLRP3, others)

• Cytolytic innate responses involve type I interferons, cytokines (TNF-α, IL-1, IL-6, IL-18) innate lymphoid cells (ILCs) including natural killer (NK) cells

• Induction of anti-viral programs in target cells

• Stimulate adaptive immune response

Paroxysmal Nocturnal Hemoglobinuria

• Somatic PIGA gene variants (germline thought lethal)

• Unregulated terminal complement activation with complement-mediated RBC lysis

due to lack of inhibitors

• Major manifestations: Red/darker, urine (hemoglobinuria), Symptomatic anemia: fatigue, dyspnea, Aplastic anemia (children), thrombosis (major cause of death)

• About 35% mortality in 5 years

Eculizumab (DRUG)

• monoclonal antibody

• Binds C5, preventing cleavage to C5a and C5b, thus inhibiting the terminal complement pathway

• Helps anemia, thrombosis; improves quality of life

Hereditary Angioedema

episodes of painless swelling

• Type 1: C1 inhibitor quantitative deficiency

• Type 2: C1 inhibitor functional deficiency

• HAE with normal C1INH (once called Type 3):

- Normal C1 inhibitor level and function

Acquired angioedema

• Not hereditary

• Caused by:

- Autoantibody to C1INH

- Excessive C1 activation in certain autoimmune diseases or cancer, depleting C1INH in an otherwise normal person faster than it can be resynthesized

• A low C1q (a C1 component) suggests acquired angioedema

TLR3 and Herpes Simplex Virus I (HSV-1)

• UNC-93B is an ER protein needed for normal TLR3, TLR7, TLR8, TLR9 signaling

• Crucial for normal host response to HSV

• A gene variant causes susceptibility to Herpes simplex

viral encephalitis

Inquimod (DRUG)

- TLR7/8 agonist used clinically for anti-viral and anti-tumor therapy

Human Inborn errors of Immunity

• Gene variants in IRAK4 or MyD88

• Organisms: Streptococcus pneumoniae (79%), Staphylococcus aureus (32%), Gram negative organisms (25%)

• Those who survive don't have infections after about age

14 years

NEMO gene variant

Causes:

- incontinentia pigmenti

- anhidrotic ectodermal dysplasia (skin, conical teeth, hair)

- impaired antibody class switching (hyper-IgM phenotype) and recurrent infections

TLR4 gene variant Asp299Gly (D299G)

- 6-10% of population

• Gram-negative bacteremia and sepsis

•RSV infection

• Tonsillitis (!)

• HIV-associated TB

• Fièvre boutonneuse - fever, rash and the notorious

"tache noire"

• Inflammatory bowel disease: Crohn's disease, ulcerative colitis

• Gastric, colon cancers

• Endometriosis

Severe COVID-19

• Severe COVID-19: systemic inflammatory response causes acute respiratory distress syndrome (ARDS)

• Dysregulated, intense NLRP3 activation

• Release of pro-inflammatory cytokines (IL-6, IL-1β)

Familial Cold Autoinflammatory syndrome

• Non-urticarial rash, fever, arthralgias following exposure to cold (10 minutes to several hours)

• Autosomal dominant (1q44); NLRP3 gain-of-function gene variant; unknown why cold exposure triggers the response

• Can be treated with: canakinumab (mAb to IL-1β), rilonacept (IL-1 inhibitor), anakinra (recombinant IL-1 receptor antagonist)

Familial Chronic Mucocutaneous Candidiasis

• Various defects in the dectin-1-CARD9-Th17

(a severe yeast infection)

Chédiak-Higashi Syndrome

• Caused by a deficiency in a lysosomal trafficking

regulator protein, resulting in large cytoplasmic granules

• Neutrophils have trouble with diapedesis, and other

functional abnormalities

• Patients typically have silvery blond hair and blue eyes

Chronic Granulomatous Disease (CGD)

X-LINKED RECESSIVE AND AUTOSOMAL RECESSIVE (XLR MOST COMMON)

- deficiency of any subunit of NADPH oxidase

• Boils, abscesses, pneumonia, osteomyelitis

• Delayed separation of the umbilical cord (also seen in

other neutrophil disorders)

• Respiratory burst can be evaluated in the lab

- DHR (dihydrorhodamine) assay: current

Mendelian Susceptibility to Mycobacterial Disease (MSMD)

• The normal host defense to mycobacteria depends (in part) on the IL-12, IFN-gamma pathway in innate immunity

• Patients with defects in this pathway develop infections with normally weakly- virulent mycobacteria (BCGosis; Salmonella; sometimes TB)

ADA Deficiency

AUTOSOMAL RECESSIVE

• enzyme involved in nucleotide metabolism

• When deficient, toxic nucleotide metabolites accumulate, interfering with lymphocyte and NK cell development

• ADA deficiency produces a SCID-like clinical presentation ("T- B- NK-")

• treated by ADA replacement, or HSCT

X-linked agammaglobulinemia type 1 (XLA1)

X-LINKED RECESSIVE

• important signaling molecule, Bruton tyrosine kinase (BTK), in the checkpoint process is non-functional

• BTK is important for mast cell function (other immune use it but not vital for function)

• Affected B cells make very abnormal heavy chains and do not mature correctly -> not detected in peripheral blood

• Patients have low levels of non-functional antibody, and present with recurrent infections

• BTK inhibitors (-brutinibs) used clinically for B cell cancers, chronic urticaria; clinical trials for mastocytosis and other mast cell disorders

Autoimmune Polyendocrinopathy Syndrome,

Type 1 (APS-1)

• The AIRE gene oversees the thymic self MHC-peptide library -> AIRE gene variant causes APS-1

• Patients develop various autoimmune diseases, often involving the endocrine system (e.g., Addison disease), and chronic candidiasis; Th17 cytokines involved

TREC (T cell receptor excision circles) counting

• Counting TRECs is part of the newborn screen in all 50 states

-> A low TREC count indicates some problem with T cell development

- >One serious cause is severe combined immunodeficiency (SCID)

RAG-1 or RAG-2 deficiency

• A gene variant in either of these causes defective receptors in both T/B cells, causing one form of SCID

• NK cells have no immune receptors and are unaffected

Omenn Syndrome ('leaky SCID')

• Caused by gene variants in RAG1, RAG2, or Artemis

• Erythroderma, eosinophilia, lymphadenopathy, alopecia,

hepatosplenomegaly

• Some T cells present, but restricted repertory; B cells

undetectable; NK cells present

• IgGAM decreased but not IgE

Ataxia-telangiectasia

AUTOSOMAL RECESSIVE

• Pervasive defect in DNA repair mechanisms throughout the body

- Patients are susceptible to malignancy

- Very sensitive to ionizing radiation (X-rays limited)

• Ataxia presents before telangiectasias, immunodeficiency, and malignancy

• Elevated alpha-fetoprotein (AFP)

CD3 Deficiency

AUTOSOMAL RECESSIVE

• CD3 is a part of the T cell receptor complex that helps with signal transduction

• Gene variants cause SCID with a flow cytometry SCID phenotype of T- B+ NK+ (CD3 isn't used by B cells or NK cells)

Burkitt's Lymphoma

• Cutting and pasting DNA is treacherous

• Checkpoints sometimes fail and abnormal cells escape

• If cutting and pasting causes DNA to go to the wrong place, the result can be unchecked B cell (or T cell) growth - i.e., cancer

• Translocation of the MYC gene (chromosome 8) to the immunoglobulin HC region on chromosome 14 (or to one of the light chain chromosomes) causes unregulated MYC expression, leading to Burkitt's lymphoma

Rheumatic Fever

• Occurs when the body makes an immune response to the organism, Streptococcus pyogenes (strep throat)

• If anti-Strep antibodies cross-react with human heart, joint (and other) antigens (also called molecular mimicry), you get a 'Type 2' hypersensitivity reaction that can destroy heart valves

FcRn

• Helps protect circulating IgG from endosomal degradation

- A patient with defective FcRn will have a short IgG serum half-life

• Facilitates active transport of maternal IgG to the fetus via the placenta

- A term baby should have an equal or higher IgG level than the mother

Transient hypogammaglobulinemia of infancy

• A delay in immune system maturation + normal decline in maternal Ab levels causes low total IgG level

- The serum half-life of IgG is about 21 days

• This happens at a few months of age/resolves with time

Immune Complexes, SLE, and Complement Deficiency

• In SLE, massive immune complex forma/on is one of the major mechanisms of potentially fatal renal failure

• The complement system tries to deal with them but can't keep up; complement can get consumed faster than it is replaced

• Conversely, some patients with certain deficiencies of the early complement components can't effectively tag normal immune complexes, so they develop lupus-like diseases

Tryptase

• An elevated serum tryptase level is a clinically useful biomarker of mast cell activation (anaphylaxis, mastocytosis)

HLA Typing

• Transplant matching

• Paternity testing

• Predicting adverse drug reactions

• Certain diseases have HLA associations

- Classic example: association of (some forms of) HLA-B27 with certain types of arthritis

• Forensic (e.g., a murder investigation) analysis (DNA currently used more often)

Abacavir

• The HIV drug abacavir can cause noteworthy Type IV hypersensitivity reac1ons

• Patients who have HLA-B57 (more precisely, HLA-B*5701) are at a greater risk for reactions

• The FDA recommends screening all pa1ents for the HLA-B*5701 allele prior to initiating therapy

Bare Lymphocyte Syndrome Type I (BLS I)

AUTOSOMAL RECESSIVE

• TAP deficiency

-> TAP is a heterodimer made up of TAP1 and TAP2

• A TAP defect causes a variant of BLS with poor

CD8 T cell responses

Bare Lymphocyte Syndrome Type II

AUTOSOMAL RECESSIVE

• Defec1ve synthesis of HLA molecules can be caused by several different genetic defects, including gene variants in the transcription factors regulating MHC Class II expression

• The defects can also affect expression of Class I molecules

Conjugate Vaccines

• Many clinically relevant bacterial antigens are polysaccharides

• B cell receptors recognize polysaccharide antigens, and bring them in by receptor-mediated endocytosis

-> no peptides to attach to an MHC Class II molecule for T cell presentation

• The immune response to these antigens depends on T-independent activation

• Covalently bind small immunogenicity protein to the bacterial polysaccharide

Wiskott-Aldrich Syndrome

X-LINKED RECESSIVE

• The WAS protein regulates actin polymerization in the cytoskeleton of various cell types, including platelets and lymphocytes

• WAS deficiency causes microthrombocytopenia, eczema and recurrent infections mostly due to poor Tcell function

• Microthrombocytopenia found in only 2 conditions: WAS and x- linked thrombocytopenia; both caused by variants in the same gene (WAS)

Thymic Stromal Lymphopoetin (TSLP)

specialized cytokine (alarmin) of innate immune system produced by airway epithelial cells

- can signal ILC1 cells (causing T2-low inflammation) and/or ILC2 cells, causing eosinophilic inflammation (T2-high inflammation)

• Tezepelumab is a therapeutic monoclonal antibody, used to treat patients with severe asthma

Hyper IgE Syndrome Type 1

AUTOSOMAL DOMINANT

• PaTents develop Staphylococcus aureus, candida, and other infections of skin/lower respiratory tract; lung abscesses, pneumatocoele formation

• A STAT3 gene variant makes T cells unable to produce IL-17

Common Gamma Chain Deficiency

X-LINKED RECESSIVE

• The receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 share a

common gamma chain

-> A common gamma chain (γc) gene variant causes all of

these receptors not to work

• The result is SCID

• The flow cytometry SCID phenotype is T- B+ NK-; T cells

and NK cells need these cytokine receptors, but B cells

do not