A 34-year-old woman comes to the physician because of a 3-month history of fatigue and a 4.5-kg (10-lb) weight loss despite eating more than usual. Her pulse is 115/min and blood pressure is 140/60 mm Hg. Physical examination shows warm, moist skin, and a diffuse, non-tender swelling over the anterior neck. Ophthalmologic examination shows swelling of the eyelids and proptosis bilaterally. Which of the following is the most likely cause of this patient's symptoms?

Thyrotropin receptor autoantibodies

Constitutively active TSH receptor

Parafollicular cell hyperplasia

Thyroid peroxidase autoantibodies

Nongranulomatous thyroid inflammation

A 32-year-old woman presents with a 3-month history of intermittent blurred vision and problems walking. The patient states that she often feels “pins and needles” in her legs that cause her problems when she’s walking. The patient is afebrile, and her vital signs are within normal limits. An autoimmune disorder is suspected. Which of the following findings would most likely be present in this patient?

Damaged myelin sheath and myelin-producing cells

Destruction of blood-brain barrier

Degeneration of anterior horn cells

Decreased cerebrospinal fluid due to destruction of cells

A 21-year-old female presents to her obstetrician because she has stopped getting her period, after being irregular for the last 3 months. Upon further questioning, the patient reveals that she has had a 17 lb. unintended weight loss, endorses chronic diarrhea, abdominal pain, and constipation that waxes and wanes. Family history is notable only for an older brother with Type 1 Diabetes. She is healthy, and is eager to gain back some weight. Her OBGYN refers her to a gastroenterologist, but first sends serology laboratory studies for IgA anti-tissue transglutaminase antibodies (IgA-tTG). These results come back positive at > 10x the upper limit of normal. Which of the following is the gastroenterologist likely to find on endoscopy and duodenal biopsy?

Villous atrophy with crypt lengthening and intraepithelial lymphocytes

Friable mucosal pseudopolyps with biopsy notable for crypt abscesses

Cobblestoning with biopsy showing transmural inflammation and noncaseating granulomas

Foamy macrophages, which stain PAS positive

Normal appearing villi and biopsy

A 35-year-old man presents with large tense blisters on the flexor surfaces of the upper extremities and trunk. The histologic findings show subepidermal blisters with an eosinophil-rich infiltrate. What is the most likely underlying pathology?

Linear band of immunoglobulin G (IgG) in the epidermal basement membrane

Linear band of IgA in the basement membrane

Granular deposits of immunoglobulin A (IgA) in the dermal papilla

A 23-year-old woman comes to the physician because of a 2-month history of diarrhea, flatulence, and fatigue. She reports having 3–5 episodes of loose stools daily that have an oily appearance. The symptoms are worse after eating. She also complains of an itchy rash on her elbows and knees. A photograph of the rash is shown. Further evaluation of this patient is most likely to show which of the following findings?

Elevated exhaled hydrogen concentration

Microcytic, hypochromic red blood cells

Elevated urine tryptophan levels

PAS-positive intestinal macrophages

A 51-year-old woman with hyperlipidemia comes to the physician because of weakness for one month. At the end of the day, she feels too fatigued to cook dinner or carry a laundry basket up the stairs. She also complains of double vision after she reads for long periods of time. All of her symptoms improve with rest. Her only medication is pravastatin. Physical examination shows drooping of the upper eyelids. Strength is initially 5/5 in the upper and lower extremities but decreases to 4/5 after a few minutes of sustained resistance. Sensation to light touch is intact and deep tendon reflexes are normal. Which of the following best describes the pathogenesis of this patient's condition?

Type II hypersensitivity reaction

Organ-specific autoimmune diseases for USMLE Step 2 CK: High-Yield Pathology Lessons

Endocrine Autoimmunity - Hormonal Havoc

Pathogenesis of Autoimmune Thyroid Diseases

Hashimoto's Thyroiditis (Hypothyroidism):
- Antibodies: Anti-thyroid peroxidase (anti-TPO), anti-thyroglobulin.
- Mechanism: CD8+ T-cell cytotoxicity & antibody-mediated destruction of follicular cells.
- Pathology: Lymphocytic infiltrate with germinal centers; Hürthle cell metaplasia.
Graves' Disease (Hyperthyroidism):
- Antibody: Thyroid-Stimulating Immunoglobulin (TSI), a TSH-receptor antibody.
- Mechanism: Type II hypersensitivity where antibodies stimulate the TSH receptor, leading to ↑T3/T4.
Type 1 Diabetes Mellitus:
- Antibodies: Anti-GAD65, islet cell autoantibodies.
- Mechanism: T-cell mediated destruction of pancreatic β-cells.

⭐ Graves' disease exophthalmos is caused by T-cell infiltration and fibroblast proliferation in orbital tissues, not by direct thyroid hormone effects.

GI & Hematologic - Gut Feelings

Celiac Disease
- Patho: Immune response to gluten (gliadin) in genetically susceptible individuals (HLA-DQ2/DQ8).
- Antibodies: IgA anti-tissue transglutaminase (tTG), anti-endomysial, anti-deamidated gliadin peptide.
- Histo: Villous atrophy, crypt hyperplasia, intraepithelial lymphocytes.
Pernicious Anemia
- Patho: Autoimmune gastritis; T-cell mediated destruction of gastric parietal cells.
- Antibodies: Anti-parietal cell, anti-intrinsic factor (more specific).
- Effect: ↓ Intrinsic factor → Vitamin B12 deficiency → Megaloblastic anemia.

⭐ Dermatitis herpetiformis (pruritic papules/vesicles on extensor surfaces) is the specific skin manifestation of Celiac Disease.

Celiac Disease: Villous Atrophy vs. Normal Mucosa

Neurologic Syndromes - Nerve-Wracking

Multiple Sclerosis (MS): Central (CNS) demyelination.
- Autoimmune T-cell response to myelin basic protein. Type IV HSR.
- Sx: Optic neuritis, internuclear ophthalmoplegia (INO), sensory deficits separated in time & space.
- Dx: ↑ IgG (oligoclonal bands) in CSF, periventricular plaques on MRI.
Myasthenia Gravis (MG): Peripheral (PNS) neuromuscular junction.
- Autoantibodies to postsynaptic ACh receptors. Type II HSR.
- Sx: Ptosis, diplopia, muscle weakness worsening with use.
Guillain-Barré Syndrome (GBS): PNS demyelination.
- Molecular mimicry (often post-Campylobacter jejuni).
- Sx: Symmetric ascending paralysis/weakness.

⭐ Myasthenia Gravis is strongly associated with thymoma or thymic hyperplasia (~75% of cases).

Neurological manifestations of autoimmune diseases

Dermatologic Issues - Skin Deep Trouble

Pemphigus Vulgaris vs. Bullous Pemphigoid: Autoimmune blistering diseases differentiated by the level of skin separation.

Feature	Pemphigus Vulgaris	Bullous Pemphigoid
Antigen	Desmoglein 1 & 3 (in desmosomes)	Hemidesmosomal proteins
Blister Level	Intraepidermal	Subepidermal
Clinical	Flaccid, easily ruptured bullae; oral mucosa common; + Nikolsky sign	Tense bullae; oral mucosa rare; - Nikolsky sign
IF Pattern	Reticular (net-like)	Linear at dermal-epidermal jxn

⭐ Exam Favorite: Oral mucosal involvement is common in Pemphigus Vulgaris and rare in Bullous Pemphigoid, a key clinical differentiator.

📌 Mnemonic: Bullous is Below the epidermis (subepidermal) and blisters are Bound-down and tense.

High‑Yield Points - ⚡ Biggest Takeaways

Hashimoto's thyroiditis: Anti-TPO & anti-thyroglobulin Abs lead to hypothyroidism.

Graves' disease: Thyroid-stimulating immunoglobulin (TSI) causes hyperthyroidism.

Type 1 Diabetes: T-cell mediated destruction of pancreatic β-cells.

Myasthenia Gravis: Antibodies block postsynaptic ACh receptors at the NMJ.

Goodpasture Syndrome: Abs against Type IV collagen in kidney & lung basement membranes.

Pernicious Anemia: Anti-intrinsic factor Abs cause vitamin B12 deficiency.

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