FD Exam 2: Autoimmune Disorders and Immunodeficiencies

Multiple Sclerosis

• Cause: CD4+ T cells cause demyelination or destruction of the myelin sheaths surrounding CNS nerve axons resulting in lesions in white matter (type IV hypersensitivity)

• Clinical Presentation: numbness, tingling, blurry vision, double vision, partial vision loss, muscle weakness, difficulty walking, poor coordination, fatigue, brain fog, memory loss

Graves’ Disease

• Cause: anti-TSH receptor autoantibodies stimulation overproduction of T3 and T4 (type II hypersensitivity)

• Clinical Presentation: weight loss, heat intolerance, excessive sweating, palpitations, insomnia, trembling hands, goiter, hair loss, swollen or protruding eyes, dry eyes, sensitivity to light

Systemic Lupus Erythematous (SLE)

• Cause: autoantibodies target cellular products such as DNA, RNA, and histones leading to immune complexes that damage the kidneys, joints, and vasculature (type III hypersensitivity); autoantibodies bind neutrophils leading to their destruction (type II hypersensitivity)

• Clinical Presentation: fatigue, fevers, joint pain, joint stiffness, arthritis, butterfly or major rash across the cheeks and bridge of the nose, scene lesions that worsen in sunlight, hair loss, mouth sores, chest pain (pleuritis or pericarditis), kidney inflammation

Type I Diabetes Mellitus

• Cause: CD4+ T cells and CTLs kill the beta cells in the Langerhans’ islet of the pancreas (type IV hypersensitivity)

• Clinical Presentation: extreme thirst, frequent urination, unexplained and sudden weight loss, constant hunger, extreme fatigue, blurry vision, slow-healing sores

Pernicious Anemia

• Cause: autoantibodies bind and destroy the intrinsic factor needed for the transport of vitamin B12 across the intestinal mucosa leading to abnormalities in erythropoiesis (type II hypersensitivity)

• Clinical Presentation: numbness and tingling in the hands and feet, difficulty walking, memory loss, mood changes, extreme fatigue, pale sin, shortness of breath, smooth and red tongue (glossitis)

Goodpasture Syndrome

• Cause: autoantibodies bind to the basement membrane causing damage most notably in the kidneys and lungs (type II hypersensitivity)

• Clinical Presentation: hemoptysis, shortness of breath, chest pain, blood or protein in urine, swelling in the legs or face, rapid decrease in urine output, fatigue, fever, nausea, pale skin

Myasthenia Gravis

• Cause: autoantibodies bind to the acetylcholine receptor causing poor signal transduction to the muscles (type II hypersensitivity)

• Clinical Presentation: muscle weakness, ptosis, diplopia, difficulty chewing, dysphagia, slurred or nasal speech, difficulty breathing

Rheumatoid Arthritis

• Cause: autoreactive Th1 and Th17 play a role in joint destruction (type IV hypersensitivity); RA factor binds IgG and anti-citrullinated protein antibodies (binds modified proteins; type III hypersensitivity)

• Clinical Presentation: joint stiffness (worse in the mornings or after periods of inactivity; symmetrical impact), fatigue, low-grade fever, loss of appetite, inflammation of the skin, eyes, lungs, and heart

X-Linked Infantile Agammaglobulinemia

• Cause: mutation in the BTK gene prevents maturation of B cells and impairs production of antibodies

• Clinical Presentation: frequent, severe, and recurrent infection (i.e., otitis media, pneumonia, sinusitis, skin infections, meningitis, chronic diarrhea)

Mu Heavy Chain Deficiency

• Cause: production of abnormal, truncated IgM heavy chains without associated light chains

• Clinical Presentation: exhibit symptoms similar to CLL or SLL; splenomegaly, hepatomegaly, abdominal lymphadenopathy, fever, infection

Selective IgA Deficiency

• Cause: undetectable levels of IgA in the blood and bodily secretions

• Clinical Presentation: frequent infections (i.e., otitis media, sinusitis, bronchitis, pneumonia, GI infections), higher risk of developing autoimmune diseases (i.e., celiac disease, type I diabetes, RA, SLE), strong association with allergic rhinitis, eczema, and asthma

IgG Subclass Deficiencies

• Cause: normal total IgG levels, but deficient levels of one or more of the four IgG subclasses (IgG1, IgG2, IgG3, IgG4)

• Clinical Presentation: frequent infections (i.e., bacterial infections, pneumonia, sinusitis, bronchitis, otitis media, GI infections)

Common Variable Immunodeficiency

• Cause: genetic disorder in which B cells fail to properly mature leading to abnormally low levels of protective antibodies making individuals highly vulnerable to recurrent bacterial and viral infections

• Clinical Presentation: recurrent infections (i.e., otitis media, sinusitis, respiratory infections/pneumonia), chronic diarrhea, abdominal pain, malabsorption, enlarged lymph nodes or spleen

DiGeorge Syndrome

• Cause: 22q11.2 deletion leading to structural anomalies and thymic hypoplasia leading to the underdevelopment of T cells and immune system issues

• Clinical Presentation: frequent infections, ventricular septal defects, small ears, small chin, hooded eyelids, cleft palate, hypocalcemia

T Cell Receptor/CD3 Defects

• Cause: mutations in the CD3 subunits leaving to impaired TCR signaling and T cell development

• Clinical Presentation: early-onset recurrent infections (i.e., respiratory and GI infections), autoimmune cytopenias, thyroiditis, severe colitis

Hyper IgE/Job’s Syndrome

• Cause: random or inherited mutation in the STAT3 gene leading to defects in immune and skeletal system development; individuals will have high levels of IgE and eosinophils

• Clinical Presentation: skin rashes and boils, chronic bacterial or fungal lung infections, high bone flexibility, severe joint mobility, tendency for fractures, scoliosis, dental issues, prominent forehead, deep-set eyes, broader nasal bridge

Chronic Mucocutaneous Candidiasis

• Cause: genetic mutation (dominant → STAT1; recessive → AIRE) leading to deficient IL-17 causing persistent or recurrent Candida fungal infections of the skin, nails, and mucous membranes

• Clinical Presentation: persistent oral thrush, thickened/discolored nails, thick and crusted rashes on the face or scalp

IL-2 Receptor Deficiency

• Cause: mutations in the components of the IL-2 receptor complex (gamma, alpha, or beta chains) leading to profound immune dysfunction

• Clinical Presentation: early-onset severe infection (bacterial, viral, fungal), severe enteropathy (diarrhea), failure to thrive, dermatitis/eczema, lymphadenopathy

Severe Combined Immunodeficiency Disorders

• Cause: rare genetic disorders where individuals are born with little to no functional immune system; mutations in multiple genes that are required for the development and function of T cells, B cells, and NK cells

• Clinical Presentation: recurrent infections (bacterial, viral, fungal), chronic diarrhea, persistent oral thrush, frequent and severe pneumonia, meningitis, failure to thrive (poor growth)

X-Linked SCID/gamma-c Deficiency

• Cause: mutation in the IL2RG gene leading to a lack of functional T and NK cells

• Clinical Presentation: appears in early infancy (3-6 months), persistent infections, poor growth, chronic diarrhea, thrush, severe skin rashes

Adenosine Deaminase SCID

• Cause: mutations in the ADA gene leading to a deficiency in the ADA enzyme, causing toxic metabolites to build up in cells and a complete lack of B and T lymphocytes

• Clinical Presentation: presents before 6 months, severe infections (pneumonia), chronic diarrhea, widespread skin rashes, failure to thrive

RAG Deficiency SCID

• Cause: mutations in the RAG1 or RAG2 genes, which are essential for developing functional T and B lymphocytes

• Clinical Presentation: recurrent infections, rash, diarrhea, hepatosplenomegaly, lymphadenopathy

Bare Lymphocyte Syndromes

• Cause: genetic mutations (TAP1 or TAP2) cause immune cells to fail to produce major histocompatibility complex (MHC) proteins

• Clinical Presentation: recurrent infections, chronic diarrhea, failure to thrive

Hyper-IgM Syndrome

• Cause: mutation in the CD40LG gene causing low levels of protective IgG, IgA, and IgE antibodies but normal or elevated levels of IgM

• Clinical Presentation: present within first year of life, recurrent pneumonia, sinusitis, ear infections, diarrhea

Ataxia Telangiectasia

• Cause: mutation in the ATM gene causing a neurodegenerative disorder that impacts the nervous, immune, and other body systems; impairs the body’s ability to repair broken DNA

• Clinical Presentation: difficulty with coordination and balance, slurred speech, involuntary muscle jerks, oculomotor apraxia, red “spider veins” (telangiectases) on sun-exposed skin, chronic or severe recurrent respiratory and sinus infections, high risk of cancer

Wiskott-Aldrich Syndrome

• Cause: mutation in WAS gene on X chromosome which regulations production of WAS protein which is crucial for immune signaling and platelet formation

• Clinical Presentation: microthrombocytopenia, easy bruising, petechiae, nosebleeds, recurrent infections, susceptible to autoimmune diseases and cancers (i.e., lymphomas), eczema

Congenital Agranulocytosis

• Cause: characterizes by an absence or severe shortage of neutrophils; caused by mutations in genes such as HAX1, ELANE, GFI1, CSF3R

• Clinical Presentation: recurrent infections (i.e., skin, lungs, skin, liver), bone density loss (osteopenia or osteoporosis), elevated risk of developing myelodysplastic syndrome or acute myeloid leukemia

Leukocyte Adhesion Deficiency (LAD-1)

• Cause: gene mutations that prevent white blood cells from traveling through the blood and from properly adhering to sites of infection

• Clinical Presentation: delayed umbilical cord separation, recurrent infection, severe gum disease, leukocytosis

Chronic Granulomatous Disease

• Cause: gene mutations impair the production of NADPH oxidase enzyme complex resulting in phagocytes that cannot effectively kill certain bacteria and fungi

• Clinical Presentation: recurrent infections (i.e, Staph. aureus, Serratia marcescens, Burkholderia cepacia, Nocardia, Aspergillus), frequent infections and abscess sites in the lungs, liver, skin, bones, lymph nodes, and brain

Myeloperoxidase Deficiency

• Cause: characterized by reduced or absent activity of the MPO enzyme in neutrophils and monocytes, which is crucial for killing certain pathogens, particularly Candida albicans

• Clinical Presentation: mostly asymptomatic, recurrent or severe Candida infections

Chediak-Higashi Syndrome

• Cause: mutation in the LYST gene causing defects in neutrophils and NK cells impairing the ability to fight bacteria and viruses

• Clinical Presentation: recurrent infections, albinism, bleeding tendencies, peripheral neuropathy, muscle weakness, walking difficulties

Early Classical Pathway Deficiencies

• Cause: deficiencies of C1q, C1r, C1s, C4, and C2 leading to impaired immune complex clearance and a high risk of developing autoimmune diseases (i.e., SLE)

• Clinical Presentation: high association with SLE due to failure to clear apoptotic cells and immune complexes, increases susceptibility to encapsulated bacteria (i.e., Strep. pneumoniae, Haemophilus influenzae)

C3 Deficiency

• Cause: extremely low levels an integral complement protein essential for the defense against bacteria

• Clinical Presentation: recurrent and severe bacterial infection (i.e., otitis media, pneumonia, sinusitis, meningitis), increased risk of developing autoimmune diseases (i.e., SLE)

Terminal and Alternative Pathway Deficiencies

• Cause: deficiencies of C5-C9, Factor D/B leading to compromised innate immunity

• Clinical Presentation: recurrent and severe Neisseria infections (C5-C9), recurrent bacterial infections (Factor D/B)

Hereditary Angioedema

• Cause: deficiency or malfunction of the C1 inhibitor protein

• Clinical Presentation: swelling in the face, hands, feet, abdomen, and throat, unregulated activation of the complement pathway