Hyperimmunoglobulin E syndrome (HIES), also known as Job's syndrome, is a rare primary

immunodeficiency disorder characterized by recurrent infections, elevated levels of serum

immunoglobulin E (IgE), and various other clinical manifestations. The pathophysiology of hyper IgE
syndrome involves defects in both innate and adaptive immune responses, which contribute to the
susceptibility to infections and other associated features. Here's an overview of the pathophysiological
mechanisms involved:

1. Genetic Basis: HIES can be inherited in an autosomal dominant (AD) or autosomal recessive (AR)
manner, with mutations in genes associated with the immune system. The most common form,
autosomal dominant hyper IgE syndrome (AD-HIES), is primarily caused by mutations in the signal
transducer and activator of transcription 3 (STAT3) gene, which plays a crucial role in the signaling
pathways of various cytokines involved in immune regulation.

2. Impaired Th17 Cell Differentiation: STAT3 mutations impair the differentiation and function of T-
helper 17 (Th17) cells, a subset of T cells involved in defense against extracellular bacteria and fungi.
Reduced Th17 cell responses lead to decreased production of interleukin-17 (IL-17) and interleukin-22
(IL-22), which are essential for mucosal immunity and barrier function.

3. Dysregulated Immune Response: Defective Th17 cell differentiation and cytokine production result in
dysregulated immune responses, predisposing individuals with HIES to recurrent and severe infections,
particularly by Staphylococcus aureus, Streptococcus species, and various fungi (e.g., Candida species).

4. Elevated IgE Levels: Patients with HIES typically exhibit markedly elevated serum levels of
immunoglobulin E (IgE), which is often disproportionate to the degree of allergic symptoms. The
underlying mechanisms driving the hyper IgE phenotype are not fully understood but likely involve
dysregulation of B-cell differentiation and antibody production.

5. Skin Manifestations: HIES is associated with characteristic dermatological features, including eczema-
like rash, cold abscesses, folliculitis, and recurrent skin infections. The impaired skin barrier function,
combined with altered immune responses, predisposes individuals to cutaneous manifestations and skin
colonization by pathogenic microorganisms.

6. Skeletal Abnormalities: Skeletal abnormalities, such as craniosynostosis (premature fusion of skull

sutures), characteristic facies (e.g., broad nasal bridge, deep-set eyes), and dental anomalies, are
commonly observed in individuals with HIES. These features are believed to result from abnormal bone
development during embryogenesis.
7. Non-immunological Manifestations: In addition to immunological abnormalities, HIES may present
with non-immunological features, including connective tissue abnormalities, vascular abnormalities, and
developmental anomalies affecting various organ systems.

Understanding the pathophysiology of hyper IgE syndrome is essential for accurate diagnosis,
appropriate management, and genetic counseling for affected individuals and their families. Treatment
strategies typically focus on infection control, immunomodulation, and supportive care to mitigate
complications and improve quality of life.
Hyperimmunoglobulin E syndrome (HIES), also known as Job's syndrome, is a rare primary
immunodeficiency disorder characterized by elevated levels of immunoglobulin E (IgE) in the blood. The
pathophysiology of hyper-IgE syndrome is complex and involves dysfunction in the immune system,
particularly in the regulation of T lymphocytes. Here are some key aspects of the pathophysiology:

1. Defective T-Cell Function: HIES is primarily associated with a defect in T-cell function. T cells play a
crucial role in coordinating the immune response. In hyper-IgE syndrome, there is a deficiency in the
production or function of certain T-cell subsets, particularly helper T cells.

2. Th17 Cell Dysfunction: Th17 cells are a specific subset of T helper cells that play a role in immune
responses, particularly in defense against certain types of bacteria and fungi. In HIES, there is often a
defect in Th17 cell differentiation and function, leading to an increased susceptibility to infections
caused by certain bacteria and fungi.

3. Impaired Immune Regulation: The normal regulation of the immune system is disrupted in hyper-IgE
syndrome. This dysregulation can result in an exaggerated immune response to pathogens, leading to
chronic inflammation and tissue damage.

4. Elevated IgE Levels: As the name suggests, one of the hallmarks of hyper-IgE syndrome is abnormally
high levels of immunoglobulin E (IgE) in the blood. IgE is an antibody that plays a role in allergic
reactions. The exact mechanism leading to the elevated IgE levels in HIES is not fully understood, but it is
associated with the underlying immune system dysfunction.

5. Recurrent Infections: The immune system's inability to mount an effective defense against specific
pathogens makes individuals with hyper-IgE syndrome prone to recurrent and severe infections,
especially those caused by bacteria and fungi. Skin and lung infections are common manifestations.

6. Connective Tissue and Skeletal Abnormalities: Some individuals with HIES may exhibit connective
tissue and skeletal abnormalities. This can include features like characteristic facial appearance,
hyperextensible joints, and skeletal abnormalities.

It's important to note that there are different genetic forms of hyper-IgE syndrome, and the specific
genetic mutation can influence the clinical presentation and severity of symptoms. Genetic mutations in
genes like STAT3 have been associated with HIES, impacting the signaling pathways crucial for immune
cell function.
Management of hyper-IgE syndrome involves a multidisciplinary approach, including the treatment of
infections, immunomodulatory therapy, and supportive care. Genetic counseling may also be considered
for affected individuals and their families.