immuno 11: immunodeficiencies

What defines an immunodeficiency and how do infections typically present?

Increased susceptibility to infections with features like recurrent, severe, prolonged infections, infections by normal flora, or poor response to treatment.

Besides infections, what other clinical issues are associated with immunodeficiencies?

Autoimmune disease (~25%), anemia, arthritis, cancers (leukemia/lymphoma), and growth retardation.

What are the two main types of immunodeficiency and their causes?

Primary/congenital (genetic defects present at birth) and secondary/acquired (acquired due to disease, drugs, or environmental factors).

How common are primary immunodeficiencies and why are many mild?

~1 in 500 people have them, but most are mild due to redundancy in the immune system.

When do primary immunodeficiencies typically present and why are early defects worse?

Usually in childhood; early defects affect many immune cell types and are more severe

How are primary immunodeficiencies classified and which type is most common?

Cellular, humoral, combined, phagocytic, complement; humoral (antibody) deficiencies are most common (~50%).

What is SCID and what key immune component is always involved?

Severe combined immunodeficiency affecting multiple immune systems; always involves T cells.

What types of infections are patients with cellular immunodeficiencies most susceptible to and why?

Viral, fungal, and protozoal infections due to defective T cell-mediated immunity.

What is Hemophagocytic Lymphohistiocytosis (HLH) and what causes it?

A disorder of excessive macrophage activation caused by defects in CTL/NK cell killing (perforin-granzyme pathway mutations).

1 o is seen more often in patients birth – 18 mos while 2o is seen more frequently in children & adults

Explain the pathophysiology of HLH.

Failed killing of infected cells → persistent IFN-γ release → macrophage overactivation → systemic inflammation.

What are the key clinical features of HLH?

Anemia (RBC phagocytosis), cytopenias (low blood cells), splenomegaly (enlarged spleen), severe inflammation, increased infections.

How is HLH treated?

Immunosuppressants (e.g., methotrexate and dexamethasone), anti-IFN-γ therapy, chemotherapy, or bone marrow transplant.

What are the possible defects in humoral immunodeficiencies?

Absence of B cells, defective antibody production, or impaired B–T cell interaction.

What is selective IgA deficiency and what causes it?

Most common PI caused by failure of B cells to differentiate into IgA-secreting plasma cells.

What are the lab findings in selective IgA deficiency?

Low IgA with normal IgG, IgM, and normal B cell numbers.

What are the symptoms and treatment of selective IgA deficiency?

Recurrent mucosal infections (GI/respiratory); treated with antibiotics as needed.

What is the role of AID- Activation-Induced (Cytidine) Deaminase (AID) Hyper IgM Syndrome 2 in B cells and what happens if it is defective?

AID enables class switching; defect → inability to switch → mainly IgM production.

hat are the lab findings and symptoms of AID Hyper-IgM syndrome?

lack of switched isotypes ▪ # of peripheral B cells is normal

Normal/high IgM with low IgG/IgA; recurrent infections and possible hemolytic anemia.

How is AID Hyper-IgM syndrome treated?

IVIg replacement and antibiotics.

What causes X-linked Hyper-IgM XHIGM syndrome and how does it affect immunity?

Mutation in CD40L on CD4+ T cells prevents B cell class switching.

What are the lab findings in X-linked Hyper-IgM syndrome?

High/normal IgM, low IgG/IgA, normal B and T cell counts.

What are the symptoms and treatment of X-linked Hyper-IgM syndrome?

Opportunistic infections; treated with IVIg or bone marrow transplant.

What is Chronic Granulomatous Disease (CGD) and what causes it?

AKA: Bridges–Good syndrome

Defect in enzymes that kill pathogens in phagolysosomes → microbes survive.

What is the pathophysiology of CGD?

Persistent infection → macrophages fuse → granuloma formation.

What are the symptoms and treatment of CGD?

Recurrent bacterial/fungal infections, oral/gum disease, soft tissue infections; treated with prophylactic antimicrobials.

What types of defects occur in complement immunodeficiencies?

Deficiencies in complement proteins, receptors, or regulatory proteins.

Which complement deficiency is most severe and why? most common?

C3 deficiency because it is central to all complement pathways.

C2 deficiencies are the most common

What diseases are associated with C1, C2, or C4 deficiencies?

little to no increase in infections

Immune complex diseases such as SLE, RA, and vasculitis.

What infections are associated with C5–C9 (MAC) deficiencies?

Recurrent Neisseria infections.(meningitidis & gonorroheae)

What happens in C3 inhibitor deficiency?

increased susceptibility to encapsulated bacterial pathogensv

What happens in C1 inhibitor deficiency?

Uncontrolled complement activation → bradykinin-mediated edema (hereditary angioedema).

What defines secondary immunodeficiency and what are common causes?

Acquired immune dysfunction due to factors like infections, cancer, drugs, or systemic conditions.

What non-biologic factors contribute to secondary immunodeficiency?

Age, stress, and alcoholism.

What are common biologic causes of secondary immunodeficiency?

HIV, diabetes, cancer, chemotherapy, and immunosuppressive therapy.

What is the most well-known biologic and non-biologic cause of immunodeficiency?

HIV/AIDS.Malnutrition.

How can you distinguish humoral vs cellular immunodeficiencies clinically?

Humoral → bacterial/mucosal infections; cellular → viral, fungal, protozoal infections.

Why do defects in T cells often lead to more severe disease than B cell defects?

T cells regulate multiple immune responses, including B cell activation and macrophage function.