Overview of Histiocytic and Dendritic Cell Disorders

Origin of Histiocytes and Dendritic Cells 

Histiocytes 

• Activated tissue macrophages. 
• Characteristic histiocytic marker:  Cd68+ 
• Myeloid lineage.
  • CD11C may be positive.
• Disorders associated
  • HLH 
  • RDD: Sinus histiocytosis with massive lymphadenopathy. 

Dendritic cells, also called MDC

• Professional APC to T cell. 
• Lineage 

Myeloid lineage (CD11C+) 

• Present in stratified epithelium.
  • Skin and mucous membrane. 
  • Langerhans cells are found. 
  • Characteristic features: CD1A+ and tennis racket-shaped granules are found under electron microscopy called BIRBECK granules. 
  • The disorder associated is LCH. 
• Present in tissues except stratified epithelium.
  • Interstitial dendritic cells are found. 
  • Disorders associated with JXG, Erdheim-Chester disease. 

• Dendritic cells found in blood circulation. 
• DC-1 or MDC are present. 
• Lymphoid lineage (CD11C-)
  • Plasmacytoid dendritic cells resemble plasma cells. 
  • Function: Secret Type I IFN or IFN α.
  • Seen in circulation. 
  • Associated with SLE

• CD1A+ and BIRBECK granules are not seen in interstitial dendritic cells and DC-1 cells.
• The key cell involved in the pathogenesis of SLE is. PDC 
• Key molecule involved in SLE: -IFN α

Also read: Preventing Autoimmune Disorders: Recent Research on Omega-3

HLH (Hemo Phagocytic Lympho Histiocytosis)

• HLH is nothing but the histiocytes in the bone marrow that phagocytose the blood-forming cells like RBCs, WBCs, and stem cells; hemophagocytic lympho histiocytosis results in lymphocytopenia or pancytopenia.

Pathogenesis 

• Activation of histiocytes, along with the activation of NK cells and CD8 T killer cells, which enables massive cytokine storms. 
• Secretion of IL6, IL10, IL-12, Sol-IL2R, and IFN Ɣ (key element).

Etiology 

Inherited Seen in infants of <3 years of age.

• Familial HLH
  • Perforins and granzymes are two important enzymes to kill the other cells by NK and CD8 T killer cells. 
  • Genes affected are associated with the synthesis and secretion of perforins and granzymes. 
  • Genes: PRF1 (Important), UNC13D, STX11, STXBP2 
• Immunodeficiency-associated HLH
  • Griscelli syndrome 
  • CHS 
  • CGD 
  • CD27 deficiency 
  • X MEN disease 
  • Hermansky pudlak syndrome

Also read: Basics of Neutrophils And Disorders of Neutrophils

Acquired - Common in Adults.

• Infections
  • Viral
    • HHV-8/HIV/CMV/EBV 
  • Bacterial 
  • TB/Leishmania/Typhoid 
  • Malaria 
• Auto-Immune: Called as Macrophage activation syndrome 
• Malignant process
  • Leukemias and lymphomas.

Criteria for Diagnosing HLH

3 Groups of Criteria for Diagnosing HLH 

Clinical 

• Fever persisting for 7 days. 
• Splenomegaly.

 Laboratory 

• Cytopenia with the minimum of two lineages. 
• High TG (≥ 265) 
• Low fibrinogen (<150 mg/dl) 
• Very high Ferritin (>500) 
• Difficult to be found;
  •  Very low NK cell activity 
  • Very high SOL-IL2R or CD25 in the blood.

Histological 

• Evidence of hemophagocytosis. 
• ≥ 5/8, then it is HLH. 
• The HLH image shows histiocytes engulfed lots of cells like RBCs, WBCs, and their precursors. 

Treatment of HLH

• Treatment of secondary causes in adults. 
• If no good response
  • HLH2004 protocol
    • HLH94: Steroids (Dexamethasone) + Etoposide. 
    • Cyclosporine
    • Others 
  • Rituximab (CD20-Mab)
  • Alemtuzumab (CD52-Mab)
  • Emapalumab, against IFN Gamma.
• HLH94 is preferred over the HLH2004 protocol.

Also read: Feeding &amp; Eating Disorders in Infants: Types &amp; Management

Rosai Dorfman Disease (RDD)

• Sinus histiocytosis with massive lymphadenopathy.
  • Cervical lymphadenopathy(massive) 

Diagnosis: Biopsy 

• Histiocytes increased in number within the lymphnode sinus (nonmalignant proliferation). 
• CD68+ve 
• S-100+ve 
• CD1A -ve

Treatment 

• Steroids (reduce the proliferation of histiocytes) +/- Clofarabine (bone/orbit lesions). 

Other features 

• High TC, high ESR, hypergammaglobulinemia, typically polyclonal anaemia.

LCH (Langerhans Cell Histiocytosis)

• Most important in histiocytes and dendritic cell disorders.
• Clonal proliferation of LC, a dendritic cell disorder.
• Infant or a child with skin lesions like eczema is not responding to treatment given by pediatricians and dermatologists, but a biopsy revealed CD1A+ cells (LC) +/- bone lesions (punched-out lytic).
  • Single system LCH: No fever or weight loss is seen.
    • Unifocal 
    • Multifocal, Multiple, or Multisystem LCH: Fever and weight loss are seen.
    • Low-risk areas 
    • High risk zones—prognosis is poor. The areas involved are;
      • Bone marrow or Hematopoietic tissue involvement 
      • Liver 
      • Spleen 

Also read: Achalasia Cardia: Diagnosis, Types, Treatment &amp; Management

Pathophysiology

• BRAF (V600E) mutation, component of the RAS-MAPK pathway.
  • Its presence indicates a very poor prognosis and is a severe condition. 

Systems involved 

• MC-bone (80%) in the form of punched-out lytic lesions.
  • Children: Skull 
  • Adults: Jaw bone>Skull. 
  • Other bones involved in both children and adults;
    • Femur 
    • Humerus 
    • Ribs 
    • Vertebrae 

• 2nd MC system involved: skin lesions—important in children.
  • Brown-purplish papules, self-healing reticulocytosis, or Hashimoto Pritzker disease.
    • Common in infants. 
  • Eczematous rashes (more common in children and adults than infants). 
  • These presentations may be misdiagnosed for seborrheic dermatitis. 
• Other organs to be affected
  • LN (20% incidence).
    • Cervical LN are affected. 
    • Consistency 
    • Soft/matted on TB or LCH.
  • Liver and spleen
    • Hepatosplenomegaly. 
    • Primary Sclerosing Cholangitis
  • Lung: 10%
    • Usually it is smoking-related 
    • Seen in adults. 
    • Pulmonary LCH (ILD) 
  • CNS
    • MC endocrine abnormality: diabetes Insipidus + proptosis. 
  • GIT: least common involvement.
    • Children may present with diarrhoea and malabsorption.

Also read: Alcoholic Liver Disease: Symptoms, Diagnosis, Treatment &amp; Risks

Classification Systems: Outdated 

1. Letterer Siwe disease 

• Fulminant disease. 
• Age <2 years. 
• Multisystemic involvement 
• Typical features
  • High-risk organs are involved. 
  • Skin involvement resembles seborrheic dermatitis. 
  • Lytic skull lesions are seen. 
• Another name, Acute disseminated LCH, needs intensive chemotherapy. 
• In the modern era, multisystemic LCH with high-risk involvement. 

2. Hand schuller christian disease 

• Common in children 
• Characteristic triad
  • Diabetes Insipidus 
  • Skull lytic lesions 
  • Exophthalmos 
• Other names: multiple or multifocal eosinophilic granuloma may not need intensive therapy and may even go for remission. 
• High risk organs are not involved, with a relatively better prognosis compared to Letterer-Siwe disease. 
• In the modern era, multisystemic LCH with low-risk involvement.

3. Eosinophilic granuloma 

• Common in adults. 
• MC organ involved-Bone
  • MC area: skull or jaw. 
• It has an indolent course: resection +/- local radiotherapy. 
• It is due to histiocytes, but actually due to misnomer dendritic cell disorder. 
• Single-system disease with unifocal involvement 
• Eosinophilic granuloma. 
• Misnomer: Upon biopsy, the area has many eosinophils, but malignant cells are LC. 

• Pulmonary LCH - Grouped under ILD, typically affecting upper lobe with single solid lesion, typically seen in smokers: eosinophilic granuloma (Misnomer). 
• Reason: Single system unifocal lesion. 

Also read: Periarticular Disorders: Soft Tissue Rheumatism & Treatments

Treatment 

• Single system
  • Resection +/- Radiotherapy. 
  • If skin is involved, topical steroids or PUVA therapy. 
• Multisystemic involvement
  • Chemotherapy (Vinblastine, MTX, steroids, 6-MP) or intensive therapy is needed, especially if there is high-risk organ involvement. 

Diagnosis 

• Biopsy: heterogeneous collection of LC cells + eosinophils + histiocytes.
  • Tumour cell: LC. 
  • LC -
    • Nucleus 
    • Twisted towel or coffee bean appearance. 
    • CD1A+ 
    • S100+ 
    • Cd207+, also referred to as langrin. 
• Tennis racket-shaped granules are found under electron microscopy called BIRBECK granules.

Clinical Features

• Eczematous rash in the children's diaper area. Misdiagnosed as diaper rash. 
• LCH resembles and is misdiagnosed for seborrheic dermatitis. 
• Multiple punched-out lesions in children's skulls or adults—characteristic lesions of LCH. 
• Lytic lesion on the vertebral column.
• Proptosis of the left eye, biopsy from the retro orbital mass, and MRI: the condition is diagnosed as LCH. 
• Tennis racket-shaped granules are found under electron microscopy called BIRBECK granules. Distal dilatation may be or may not be seen. 

Also read: Recurrent and Autoimmune Pancreatitis

IMPORTANT POINTS

• Emperipolesis: an Intact cell seen in the cytoplasm of cells like macrophages.
• Emperipolesis may resemble HLH, but actually not. As in HLH, the cell is killed once engulfed. 
• Conditions that produce emperipolesis;
  • RDD 
  • AIH 
  • MDS 
  • MPN 
  • Lymphomas 
  • Leukemias 
• Emperipolesis is seen in two areas:
  • Megakaryocytes may engulf hematopoietic cells, commonly seen in leukemias, lymphomas, MDS, and MPN except RDD. 
  • Histiocytes engulf surrounding inflammatory cells—only seen in RDD. 

Interstitial Dendritic Cell Disorder

• JXG (Juvenile Xantho Granuloma)
  • Present in children <2 years of age. 
  • Present with solitary skin lesion yellowish, discoloration, and are seen as papules or nodules in skin.
    • Histiocytes appear foamy in nature. 
    • Xanthogranulomatous transformation. 
  • MC site: Head/Neck>Upper back 
  • Diagnosis: histopathological examination upon biopsy.
    • CD11+, CD1A-, confirms diagnosis. 
  • ECD (Erdheim-Chester disease) 
  • Multisystemic involvement like skin, bone, orbit, or retro orbital soft tissue is seen with the presence of xanthogranulomatous lesions. 
  • Bone lesions are osteosclerotic.

Also read: Menetrier's Disease: Epidemiology, Etiopathogenesis

Hope you found this blog helpful for your NEET SS Medicine Immunology Preparation. For more informative and interesting posts like these, keep reading PrepLadder’s blogs.