# Clinical Cases: Antigen Processing and Presentation

## Case 1: Bare Lymphocyte Syndrome Type II (MHC Class II Deficiency)

### Patient Demographics
- **Age:** 14 months old
- **Sex:** Female
- **Ethnicity:** North African (Moroccan descent)

### Chief Complaint
Recurrent respiratory infections and failure to thrive

### History of Present Illness
A 14-month-old girl, whose parents immigrated from Morocco, is referred for immunological evaluation after multiple hospitalizations for respiratory infections. She has had persistent diarrhea since 6 months of age and has been diagnosed with Cryptosporidium infection. She has not gained weight appropriately and has fallen from the 50th percentile at birth to below the 3rd percentile.

### Past Medical History
- Recurrent pneumonia (3 episodes since 6 months)
- Chronic diarrhea (Cryptosporidium parvum identified on stool testing)
- Oral candidiasis (persistent)
- Failure to thrive

### Birth History
- Full-term, uncomplicated delivery in Morocco
- Newborn SCID screening: Not performed (unavailable)

### Family History
- Parents are first cousins
- Older brother died at age 2 from "lung infection"
- One healthy older sister (age 5)

### Physical Examination
- **General:** Thin, wasted infant
- **Vital Signs:** T 37.8C, HR 140, RR 35
- **Growth:** Weight <3rd percentile, Length 10th percentile
- **HEENT:** Oral thrush; tonsils present but small
- **Lymphatics:** Small palpable lymph nodes
- **Lungs:** Crackles bilateral bases
- **Abdomen:** Distended, hyperactive bowel sounds

### Laboratory Workup
| Test | Result | Reference Range |
|------|--------|-----------------|
| WBC | 8,500/uL | 6,000-17,500/uL |
| Absolute lymphocyte count | 2,800/uL | 3,000-9,500/uL |
| **CD4+ T cells** | **150/uL** | 1,600-4,000/uL |
| CD8+ T cells | 1,800/uL | 560-1,700/uL |
| CD4:CD8 ratio | 0.08 | 1.0-2.5 |
| CD19+ B cells | Normal | -- |
| IgG | 250 mg/dL | 345-1236 mg/dL |
| IgA | 15 mg/dL | 14-159 mg/dL |
| IgM | 85 mg/dL | 43-207 mg/dL |
| **MHC class II expression** | **Absent on monocytes, B cells** | Present |
| MHC class I expression | Normal | -- |
| **CIITA gene** | **Homozygous mutation** | Wild type |
| HIV | Negative | -- |

### Clinical Image
![Failure to Thrive](https://upload.wikimedia.org/wikipedia/commons/thumb/b/b8/Starved_child.jpg/150px-Starved_child.jpg)

*Image showing severe malnutrition/failure to thrive pattern. Image source: Wikimedia Commons (https://commons.wikimedia.org/wiki/File:Starved_child.jpg). Public domain.*

### Diagnosis
**Bare Lymphocyte Syndrome Type II (MHC Class II Deficiency)** due to CIITA mutation.

### Discussion
Bare Lymphocyte Syndrome Type II results from defects in transcription factors required for MHC class II expression. Four complementation groups have been identified, with mutations in CIITA, RFX5, RFXAP, or RFXANK:

**Why is MHC class II deficiency so severe?**
- MHC class II is required for CD4+ T cell development in the thymus (positive selection)
- Without MHC class II, CD4+ T cells cannot mature - resulting in profound CD4 deficiency
- CD4+ T cells are required for:
  - B cell activation and antibody responses (hypogammaglobulinemia)
  - Macrophage activation (susceptibility to intracellular pathogens)
  - CTL development (impaired CD8 responses)

**Clinical features:**
- Combined immunodeficiency (affects both cellular and humoral immunity)
- Opportunistic infections (Cryptosporidium, Candida, PJP)
- Bacterial infections
- Progressive lung disease
- The inverted CD4:CD8 ratio (very low CD4, normal-high CD8) is characteristic

**Why do B cells and lymphoid tissue develop?**
- B cell development is MHC class II-independent
- Lymphoid organs form normally (unlike in some SCID variants)
- But B cells cannot receive T cell help, so antibody production is impaired

**Epidemiology:**
- More common in populations with consanguinity (North Africa, Middle East)
- Autosomal recessive inheritance

### Treatment
1. **Hematopoietic stem cell transplantation:** Only curative option
2. **IVIG:** For antibody replacement
3. **PJP prophylaxis:** TMP-SMX
4. **Aggressive infection treatment:** Including Cryptosporidium (difficult to eradicate)
5. **Nutritional support:** TPN if severe malabsorption

**Prognosis:** Without HSCT, most patients die in the first decade from infections.

---

## Case 2: Ankylosing Spondylitis (HLA-B27 Association)

### Patient Demographics
- **Age:** 28 years old
- **Sex:** Male
- **Ethnicity:** Caucasian

### Chief Complaint
Chronic low back pain and morning stiffness

### History of Present Illness
A 28-year-old man presents with a 2-year history of low back pain that began insidiously without any trauma. The pain is worst in the morning, accompanied by 2 hours of stiffness, and improves with exercise but not with rest. He has noticed decreased flexibility in his lower back. NSAIDs provide moderate relief. He also reports an episode of painful red eye 6 months ago diagnosed as acute anterior uveitis.

### Past Medical History
- Acute anterior uveitis (iritis) 6 months ago - treated with topical steroids
- No history of psoriasis, inflammatory bowel disease, or reactive arthritis

### Family History
- Father has "bad back" and required hip replacement at age 55
- Paternal uncle diagnosed with ankylosing spondylitis

### Physical Examination
- **General:** Well-appearing young man
- **Vital Signs:** Normal
- **Spine:**
  - Loss of normal lumbar lordosis
  - Reduced chest expansion (3 cm; normal >5 cm)
  - Positive modified Schober test (4 cm expansion; normal >5 cm)
  - Limited lateral flexion
  - Tenderness over sacroiliac joints bilaterally
- **Eyes:** Currently normal; history of previous iritis
- **MSK:** No peripheral joint swelling

### Laboratory Workup
| Test | Result | Reference Range |
|------|--------|-----------------|
| ESR | 45 mm/hr | 0-15 mm/hr |
| CRP | 28 mg/L | <3 mg/L |
| **HLA-B27** | **Positive** | Present in 8% of Caucasians |
| RF | Negative | -- |
| Anti-CCP | Negative | -- |
| ANA | Negative | -- |
| CBC | Normal | -- |
| Sacroiliac joint XR | Bilateral sacroiliitis (grade 2-3) | Normal |
| MRI sacroiliac joints | Bilateral bone marrow edema, erosions | Normal |

### Clinical Image
![Sacroiliitis on X-ray](https://upload.wikimedia.org/wikipedia/commons/thumb/5/53/Bilateral_sacroiliitis.jpg/220px-Bilateral_sacroiliitis.jpg)

*Image showing bilateral sacroiliitis with joint space narrowing and sclerosis, characteristic of ankylosing spondylitis. Image source: Wikimedia Commons (https://commons.wikimedia.org/wiki/File:Bilateral_sacroiliitis.jpg). Licensed under CC BY-SA 3.0.*

### Diagnosis
**Ankylosing Spondylitis** - an HLA-B27-associated spondyloarthropathy.

### Discussion
Ankylosing spondylitis (AS) is a chronic inflammatory disease primarily affecting the axial skeleton, with the strongest known HLA-disease association:

**HLA-B27 and Disease:**
- ~90% of AS patients are HLA-B27 positive
- HLA-B27 is present in only ~8% of the general Caucasian population
- Relative risk: HLA-B27+ individuals have ~100x increased risk of AS
- However, most HLA-B27+ individuals never develop AS (~5% lifetime risk)

**Proposed mechanisms for HLA-B27 association:**
1. **Arthritogenic peptide hypothesis:** HLA-B27 presents specific self-peptides that trigger autoreactive CD8+ T cells
2. **HLA-B27 misfolding:** Misfolded HLA-B27 in the ER triggers the unfolded protein response, causing IL-23 production and Th17 activation
3. **HLA-B27 homodimers:** Cell surface HLA-B27 homodimers activate NK cells and Th17 cells

**Clinical features of AS:**
- Inflammatory back pain (morning stiffness >30 min, improves with exercise)
- Sacroiliitis (hallmark finding on imaging)
- Progressive spinal fusion ("bamboo spine")
- Extra-articular manifestations:
  - Acute anterior uveitis (25-30%)
  - Inflammatory bowel disease
  - Aortitis, conduction abnormalities
  - Apical pulmonary fibrosis

**Other HLA-B27-associated spondyloarthropathies:**
- Reactive arthritis
- Psoriatic arthritis (axial)
- IBD-associated arthritis
- Juvenile spondyloarthropathy

### Treatment
1. **NSAIDs:** First-line; continuous use may slow radiographic progression
2. **Physical therapy:** Essential for maintaining mobility
3. **TNF inhibitors:** For inadequate response to NSAIDs (adalimumab, etanercept, infliximab)
4. **IL-17 inhibitors:** Secukinumab, ixekizumab - effective for AS
5. **Treatment of uveitis:** Topical steroids; biologics reduce recurrence
6. **Smoking cessation:** Smoking worsens outcomes

---

## Case 3: TAP Deficiency (Bare Lymphocyte Syndrome Type I)

### Patient Demographics
- **Age:** 16 years old
- **Sex:** Female
- **Ethnicity:** Turkish descent

### Chief Complaint
Recurrent sinopulmonary infections and chronic skin ulcers

### History of Present Illness
A 16-year-old girl of Turkish descent with a history of recurrent sinusitis and bronchiectasis presents for evaluation. She has had pneumonia yearly since age 5 and developed bronchiectasis by age 10. She also has chronic, non-healing skin ulcers on her lower legs that have been present for years and biopsied multiple times without a clear diagnosis. She has never had opportunistic infections.

### Past Medical History
- Recurrent sinusitis (5-6 episodes/year)
- Recurrent pneumonia (at least once yearly)
- Bronchiectasis (diagnosed at age 10)
- Chronic skin ulcers on lower extremities (since age 8)
- No history of viral infections, opportunistic infections

### Family History
- Parents are second cousins
- Older brother with similar respiratory infections and skin lesions

### Physical Examination
- **General:** Thin but overall well-appearing teenager
- **Vital Signs:** Normal
- **HEENT:** Nasal mucosal edema; bilateral TM scarring from prior infections
- **Lungs:** Scattered crackles; clubbing of fingers
- **Skin:** Multiple chronic granulomatous ulcers on both lower legs with raised borders
- **Lymphatics:** Normal

### Laboratory Workup
| Test | Result | Reference Range |
|------|--------|-----------------|
| WBC | 9,500/uL | 4,500-13,500/uL |
| CD8+ T cells | Markedly reduced | -- |
| CD4+ T cells | Normal | -- |
| NK cells | Normal | -- |
| IgG | 850 mg/dL | 700-1600 mg/dL |
| IgA | 180 mg/dL | 70-400 mg/dL |
| **MHC class I expression** | **<10% of normal** | Normal |
| MHC class II expression | Normal | -- |
| **TAP1 gene** | **Homozygous mutation** | Wild type |
| Skin biopsy | Granulomatous inflammation with giant cells | -- |
| Chest CT | Bronchiectasis with tree-in-bud opacities | Normal |

### Clinical Image
![Granulomatous Skin Ulcer](https://upload.wikimedia.org/wikipedia/commons/thumb/6/68/Granuloma_annulare_-_very_high_mag.jpg/220px-Granuloma_annulare_-_very_high_mag.jpg)

*Image showing granulomatous inflammation pattern similar to that seen in TAP deficiency skin lesions. Image source: Wikimedia Commons (https://commons.wikimedia.org/wiki/File:Granuloma_annulare_-_very_high_mag.jpg). Public domain.*

### Diagnosis
**TAP Deficiency (Bare Lymphocyte Syndrome Type I/MHC Class I Deficiency)** due to TAP1 mutation.

### Discussion
TAP (Transporter Associated with Antigen Processing) deficiency is a rare form of MHC class I deficiency:

**Normal TAP function:**
- TAP1 and TAP2 form a heterodimeric transporter
- TAP transports cytosolic peptides into the ER for loading onto MHC class I molecules
- Without TAP, MHC class I molecules cannot be loaded with peptides and are unstable
- Result: Markedly reduced MHC class I surface expression

**Why is the phenotype milder than MHC class II deficiency?**
- MHC class I is not required for CD8+ T cell development in the thymus (surprising!)
- CD8+ T cells can develop but are functionally impaired in the periphery
- NK cells are present and functional
- The syndrome is primarily characterized by respiratory tract infections, not opportunistic infections

**Characteristic clinical features:**
- **Recurrent bacterial sinopulmonary infections** (not opportunistic)
- **Bronchiectasis** (progressive lung damage)
- **Necrotizing granulomatous skin lesions** on legs - very characteristic
- **Generally survive to adulthood** (unlike BLS Type II)
- **NO severe viral infections** (NK cells provide some antiviral defense)

**Why granulomatous skin lesions?**
- Mechanism unclear; may represent abnormal inflammatory response
- Pathognomonic for TAP deficiency when combined with respiratory infections

### Treatment
1. **Prophylactic antibiotics:** To reduce sinopulmonary infections
2. **Aggressive treatment of infections:** Prevent progression of bronchiectasis
3. **Pulmonary rehabilitation:** Airway clearance techniques
4. **Skin lesion management:** Often refractory; may respond to topical steroids, calcineurin inhibitors
5. **HSCT:** Has been performed in severe cases, but outcomes are variable
6. **Immunoglobulin replacement:** Generally not indicated (antibody production intact)
7. **Surveillance:** Monitor for lung function decline